CTNNB1c.420T>CBenign

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Variant interpretation report

CTNNB1 c.420T>C, p.(Ile140=)

NM_001904.4:c.420T>C NP_001895.1:p.(Ile140=) View identifiers

Classification

Benign

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is benign. Select a step to read what it means.

Benign.A benign classification under the recorded framework.

In plain language

Gene-level background from the recorded interpretation.

About CTNNB1

No gene-level summary was recorded for this case.

Key facts

Evidence used: 1 stand alone (benign) · 1 strong (benign) · 1 supporting (benign)
Expert rules: Not recorded
Other laboratories (ClinVar): 3 Benign
Pipeline record: 7 Aug 2026 · version 7.1.0

Evidence considered

View criteria

Applied evidence criteria

BA1 (stand alone): Met (stand-alone benign): the variant is a common polymorphism. Its maximum population allele frequency is about 1.5% (African/African American in gnomAD v2.1 and v4.1), far above the 1% threshold expected for a severe, early-onset, predominantly de novo dominant disorder, so it cannot be a common cause of CTNNB1 syndrome.
BS1 (strong): Met (strong benign): the allele frequency (up to about 1.5% in African/African American populations) far exceeds what is expected for CTNNB1 syndrome, a severe, fully penetrant, predominantly de novo disorder. Observed homozygotes (8 in gnomAD v2.1, 17 in v4.1) are incompatible with a fully penetrant dominant disease allele.
BP7 (supporting): Met (supporting): the variant is synonymous (p.Ile140=) and splice-prediction tools indicate no effect on splicing (SpliceAI max delta 0.13, below the 0.2 threshold), with the change located deep within exon 4, away from splice consensus sites.

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

01The reasoning

How it was classified

The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 0 Benign evidence criteria: 3

Pathogenic criteria applied · 0

No pathogenic criterion marked as applied in the recorded assessment.

Benign criteria applied · 3

BA1Stand alone

BA1 · stand alone

Met (stand-alone benign): the variant is a common polymorphism. Its maximum population allele frequency is about 1.5% (African/African American in gnomAD v2.1 and v4.1), far above the 1% threshold expected for a severe, early-onset, predominantly de novo dominant disorder, so it cannot be a common cause of CTNNB1 syndrome.

BS1Strong

BS1 · strong

Met (strong benign): the allele frequency (up to about 1.5% in African/African American populations) far exceeds what is expected for CTNNB1 syndrome, a severe, fully penetrant, predominantly de novo disorder. Observed homozygotes (8 in gnomAD v2.1, 17 in v4.1) are incompatible with a fully penetrant dominant disease allele.

BP7Supporting

BP7 · supporting

Met (supporting): the variant is synonymous (p.Ile140=) and splice-prediction tools indicate no effect on splicing (SpliceAI max delta 0.13, below the 0.2 threshold), with the change located deep within exon 4, away from splice consensus sites.

Recorded classification: Benign

No gene-specific classification framework exists for CTNNB1, so the standard ACMG/AMP 2015 rules were applied. BA1 was met at stand-alone benign strength (maximum population allele frequency about 1.5% in African/African American populations, exceeding the 1% threshold), BS1 at strong benign strength (frequency far above expectation for a severe, predominantly de novo dominant disorder, with homozygotes observed), and BP7 at supporting strength (synonymous change with no predicted splicing impact). All pathogenic-direction criteria were either not met or not applicable. Under the ACMG/AMP 2015 combination rules, the single BA1 stand-alone criterion is sufficient for a Benign classification; BS1 and BP7 are consistent with and reinforce this conclusion.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

gnomAD v4.1

gnomAD v2.1

Population frequency

1,495 / 1,614,046 alleles

gnomAD v4.1: 1,495 / 1,614,046 alleles. Recorded AF 0.000926244. Recorded homozygote count 17.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 0.00182667; MAF= 0.18267%, 516/282482 alleles, homozygotes = 8) and has highest observed frequency in the African/African American population (AF= 0.0157827; MAF= 1.57827%, 394/24964 alleles, homozygotes = 8); grpmax FAF= 0.0150438.

gnomAD-Canada

This variant is present in gnomAD-Canada v1.0 (AF= 0.0013029315960912053, 24/18420 alleles, homozygotes = 0).

Applied · BA1, BS1 →

gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗

SpliceAI score

0.130 maximum delta

Recorded SpliceAI maximum delta score: 0.130. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · BP7 → SpliceAI ↗

ClinVar submissions

3 reported laboratory submissions

3 Benign. ClinVar API review status: criteria provided, multiple submitters, no conflicts.

Context only ClinVar ↗

Functional evidence

Statement recorded

OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

No listed criterion applied OncoKB ↗

COSMIC

Cancer Hotspots

Somatic evidence

3 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV104442201, n = 3 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only

COSMIC ↗Cancer Hotspots ↗

For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

28 criteria with recorded statuses: 3 met · 7 not met · 9 not assessed · 9 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic

PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5

Benign

BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7

Met Not met Not assessed Not applicable

Framework: generic ACMG/AMP 2015 fallback (Richards et al., PMID:25741868). ClinGen CSPEC not found (cspec.found=false) and no CTNNB1 VCEP materials exist in the case (vcep_materials.json final_classification_framework.found=false, framework_mode=generic_acmg).

This group (segregation_de_novo: PS2, PM6, PP1, BS4) contributes NO pathogenic and NO benign weight: all four criteria are not_assessed because the case bundle contains no proband, parental, or family segregation data for NM_001904.4:c.420T>C.

The variant is a synonymous substitution (p.(Ile140=)) classified Benign in ClinVar by 3 clinical laboratories, but ClinVar submissions carry no criterion-level assertions (all evidence_signals.criteria_found are empty) and cannot be used to infer segregation/de novo criteria.

Literature is non-contributory for this group: the only retrieved PMIDs (25741868 ACMG/AMP guidelines, 28492532 Sherloc) are methodology papers that never mention c.420T>C; no case report with de novo or segregation data exists in the case bundle.

Gap for future curation: proband-parent trio testing (PS2/PM6) and segregation testing of affected relatives (PP1/BS4) would be required before any of these criteria can be applied; the benign classification of this variant, if upheld, rests on population frequency and other evidence groups, not on this group.

No case-control enrichment (PS4) or phenotype-specificity (PP4) evidence supports pathogenicity for NM_001904.4:c.420T>C (p.Ile140=); the variant is a common synonymous change (gnomAD v2.1 AF 0.18% overall, up to 1.6% in AFR, homozygotes observed) and is absent from all disease-case literature in the bundle.

PP5 and BP6 are not met: ClinVar 709750 carries a Benign aggregate label from ordinary laboratory submissions (0 expert-panel submissions, 2 stars); per group policy only an exact-variant ClinVar expert-panel classification can trigger PP5 (Pathogenic/LP) or BP6 (Benign/LB).

BP5 not assessed: no proband genotype/phenotype data exist to evaluate an alternate molecular basis for disease.

Governing framework: no ClinGen CSPEC or VCEP specification exists for CTNNB1 (cspec.found = false, framework_mode = generic_acmg); generic ACMG/AMP 2015 combination rules (generic_acmg_combination_rules, source PMID:25741868) apply.

PM3 = not_applicable: CTNNB1 germline disease is autosomal dominant (CTNNB1 syndrome, MIM 615075; heterozygous largely de novo variants per pvs1_gene_context literature review), and PM3 requires a recessive disorder with the variant detected in trans with a pathogenic variant; no such disorder or observation exists in this case.

BP2 = not_assessed: the evidence bundle contains no proband/family genotypes, no phase (trans/cis) determinations, and no co-occurrence of c.420T>C with a pathogenic CTNNB1 variant; the observation-based benign-supporting criterion cannot be evaluated without this data.

Context (not used to decide PM3/BP2): c.420T>C is a common synonymous variant (gnomAD v2.1 AF 0.183% overall, AFR 1.578%, 8 homozygotes; gnomAD v4.1 AF 0.093%, AFR 1.497%, 17 homozygotes) and is Benign in ClinVar (3 clinical laboratories); population-frequency and ClinVar-derived criteria are adjudicated by other groups.

Governing framework: no ClinGen CSPEC/VCEP and no local custom gene framework for CTNNB1; generic ACMG/AMP 2015 rules (PMID:25741868, generic_acmg_combination_rules) apply.

Governing framework: generic ACMG/AMP 2015 (PMID:25741868) fallback. No ClinGen CSPEC (cspec found=false), no VCEP materials (vcep_materials.json: summaries={}, files_found=[], gene_vcep_dir=null), and no local custom gene framework for CTNNB1 exist in the workspace; final_classification_framework.json reports framework_mode=generic_acmg, precedence_rank 3. No VCEP supporting-material PP3/BP4 pre-assignment exists to apply.

Variant is a synonymous substitution NM_001904.4:c.420T>C (p.Ile140=) in exon 4 of CTNNB1 (MANE Select transcript), ~75 nt from both exon boundaries; gnomAD VEP consequence 'synonymous_variant'.

PP3 not met: the only applicable computational line (SpliceAI, max delta 0.13) is negative for splice impact, and the missense in-silico path (REVEL/BayesDel/aGVGD) does not apply to a synonymous variant (no scores exist). No computational support for a deleterious effect.

BP7 met (supporting): synonymous variant with no predicted splice impact (SpliceAI max delta 0.13 < 0.2, no new splice site); the 'nucleotide is not highly conserved' prong is unverified (no conservation score in bundle) and flagged needs_human_review=true.

BP4 not met: only a single computational line (SpliceAI no-impact) is available; applying it to BP4 in addition to BP7 would double-count the same prediction across criteria. A second independent line (conservation score or second splice predictor) is the identified gap.

No double-counting across sub-paths: the single SpliceAI no-impact prediction is applied once (BP7); it is not also counted toward BP4 or PP3, and gnomAD frequency is not used to support any in-silico criterion (population group owns BA1/BS1).

No RNA/splice functional evidence for this exact variant exists in the reviewed literature; none was used. The two ClinVar-cited publications are framework/background references (25741868 ACMG standards; 28492532 Sherloc), not variant-specific evidence.

Governing framework: no ClinGen CSPEC/VCEP specification exists for CTNNB1 (cspec found=false, gene_vcep_dir null, vcep_materials 'no cspec url available'); final_classification_framework confirms generic_acmg_fallback with ACMG/AMP 2015 scoring model (precedence rank 3). Generic ACMG/AMP 2015 (PMID:25741868) therefore governs, with the pipeline's non-VCEP gnomAD house thresholds (PM2<0.1%, BS1>0.3%, BA1>1% on maximum population AF).

Variant: NM_001904.4:c.420T>C = NP_001895.1:p.(Ile140=), CTNNB1 synonymous SNV, exon 4, rs3856746 (gnomAD-Canada VEP: synonymous_variant).

Population evidence: variant present in gnomAD v2.1 (AF 0.183%, AFR 1.578%, hom 8), gnomAD v4.1 (AF 0.093%, AFR 1.497%, hom 17), and gnomAD-Canada v1.0 (AF 0.13%, AFR 1.47%); grpmax FAF 1.504% (v2.1) / 1.424% (v4.1).

BA1 met (stand-alone): maximum population AF (AFR ~1.5%) exceeds the 1% non-VCEP BA1 threshold; far above any plausible allele frequency for a severe, fully penetrant, mostly de novo dominant neurodevelopmental disorder.

BS1 met (strong): AFR AF ~1.5% exceeds the 0.3% non-VCEP BS1 threshold and is orders of magnitude above the expected disease allele frequency; 8-17 homozygotes are incompatible with a fully penetrant dominant disease allele.

BS2 not met: gnomAD is not a phenotype-verified cohort, so the 'well-documented healthy adult' requirement is unsatisfied; homozygote observations (8 v2.1 / 17 v4.1) are noted and already captured under BA1/BS1.

PM2 not met: the variant is common (max population AF ~1.5%, 17 homozygotes in v4.1), far above the rarity threshold, and PM2 is mutually exclusive with the met BA1/BS1.

No criterion was inferred from ClinVar's Benign classification (3 clinical laboratories, 2-star, no expert panel) or from any other source's final classification; only primary population-frequency data were used.

Publications reviewed: PMID:25741868 (ACMG/AMP 2015 guideline, governing rule text for BA1/BS1/BS2/PM2, full text available). PMID:28492532 (Sherloc) was not consulted for population criteria; CTNNB1 disease papers (e.g., PMID:36083290) were used only for disease-severity/penetrance context, not as variant-specific population evidence.

Met · 3

BA1 Stand aloneMet (stand-alone benign): the variant is a common polymorphism. Its maximum population allele frequency is about 1.5% (African/African American in gnomAD v2.1 and v4.1), far above the 1% threshold expected for a severe, early-onset, predominantly de novo dominant disorder, so it cannot be a common cause of CTNNB1 syndrome. Details ▾Hide ▴

Reasoning

Generic ACMG/AMP 2015 (Richards et al., PMID:25741868) BA1 is the stand-alone benign criterion for allele frequency far exceeding what is expected for the disorder. No ClinGen CSPEC/VCEP specification exists for CTNNB1 (cspec found=false; framework_mode 'generic_acmg', ACMG/AMP 2015 fallback), so the pipeline's non-VCEP gnomAD house threshold applies: BA1 when the maximum population allele frequency exceeds 1%. NM_001904.4:c.420T>C (p.Ile140=, rs3856746) is present in gnomAD v2.1 at overall AF 0.183% (516/282,482 alleles, 8 homozygotes) with African/African American AF 1.578% (394/24,964 alleles, 8 homozygotes) and grpmax FAF 1.504%; in gnomAD v4.1 at overall AF 0.093% (1,495/1,614,046 alleles, 17 homozygotes) with AFR AF 1.497% (1,123/75,022 alleles, 15 homozygotes) and joint grpmax FAF 1.424%; and in gnomAD-Canada v1.0 at AF 0.13% (24/18,420) with AFR AF 1.47%. The maximum population AF (AFR, 1.50-1.58%) and grpmax FAF (1.42-1.50%) both exceed the 1% BA1 threshold. For a severe, early-onset, fully penetrant autosomal dominant neurodevelopmental disorder that is predominantly de novo, an AFR allele frequency of ~1.5% is far above any plausible disease allele frequency, so the variant cannot be a common cause of CTNNB1 syndrome. BA1 is met at stand-alone strength. (Note: literal ACMG 2015 text uses '>5%' for BA1; the 1% non-VCEP threshold is the pipeline house convention and is met here as well.)

Rule

Generic ACMG/AMP 2015 BA1 (stand-alone benign); non-VCEP house threshold: max population AF > 1% (met: AFR AF 1.50-1.58%, grpmax FAF 1.42-1.50%).

Evidence considered

gnomAD v2.1 record 3-41266623-T-C: overall AF 0.00182667 (516/282,482), AFR AF 0.0157827 (394/24,964, hom 8), grpmax FAF 0.0150438
gnomAD v4.1 record 3-41225132-T-C: overall AF 0.000926244 (1,495/1,614,046), AFR AF 0.0149689 (1,123/75,022, hom 15), joint grpmax FAF 0.0142419
gnomAD-Canada v1.0 (HostSeq) record 3-41225132-T-C: AF 0.00130293 (24/18,420), AFR AF 0.0147059
House non-VCEP gnomAD threshold BA1>1% applied to maximum population AF (variant exceeds it in AFR across all three databases)
ACMG/AMP 2015 BA1 definition (PMID:25741868): stand-alone benign criterion based on control-population allele frequency

Still missing

None for BA1 determination: max population AF (AFR 1.50-1.58%) and grpmax FAF (1.42-1.50%) both exceed the 1% non-VCEP threshold across two gnomAD releases and gnomAD-Canada.

Sources

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗generic_acmg_combination_rulesPMID:25741868 ↗

BS1 StrongMet (strong benign): the allele frequency (up to about 1.5% in African/African American populations) far exceeds what is expected for CTNNB1 syndrome, a severe, fully penetrant, predominantly de novo disorder. Observed homozygotes (8 in gnomAD v2.1, 17 in v4.1) are incompatible with a fully penetrant dominant disease allele. Details ▾Hide ▴

Reasoning

Generic ACMG/AMP 2015 (Richards et al., PMID:25741868) BS1: allele frequency in a control population that is greater than expected for the disorder is strong support for a benign interpretation of a rare Mendelian disorder. CTNNB1-associated neurodevelopmental disorder (CTNNB1 syndrome) is a severe, early-onset, fully penetrant autosomal dominant disorder, predominantly de novo, with an expected disease allele frequency far below 0.1% (largest published cohort describes 404 individuals worldwide). NM_001904.4:c.420T>C is observed in gnomAD v2.1 at overall AF 0.183% and in the African/African American population at AF 1.578% (v2.1) and 1.497% (v4.1); the maximum population AF far exceeds the 0.3% non-VCEP BS1 threshold, and grpmax FAF is 1.504% (v2.1) and 1.424% (v4.1). Even the overall AF of 0.09-0.18% is greater than expected for this disorder given its rarity and de novo predominance. Eight homozygotes (v2.1) and 17 homozygotes (v4.1) are observed, including in AFR, which is incompatible with a fully penetrant dominant disease allele. BS1 is met at strong strength based on the maximum population AF exceeding the expected disease allele frequency by orders of magnitude.

Rule

Generic ACMG/AMP 2015 BS1 (strong benign): control-population AF greater than expected for the disorder; non-VCEP house threshold: max population AF > 0.3% (met: AFR AF ~1.5%).

Evidence considered

gnomAD v2.1 record 3-41266623-T-C: AFR AF 0.0157827 (394/24,964, hom 8), grpmax FAF 0.0150438
gnomAD v4.1 record 3-41225132-T-C: AFR AF 0.0149689 (1,123/75,022, hom 15), joint grpmax FAF 0.0142419
gnomAD-Canada v1.0 (HostSeq): AFR AF 0.0147059 (15/1,020)
House non-VCEP gnomAD threshold BS1>0.3% applied to maximum population AF (met: AFR ~1.5%)
Disease context: CTNNB1 syndrome is a severe early-onset fully penetrant AD disorder, mostly de novo (pvs1_gene_context literature, PMID:36083290 404-individual cohort)

Still missing

No disease-prevalence figure with a formal carrier-frequency calculation is in the bundle; conclusion rests on the qualitative gap (severe fully penetrant dominant disorder, mostly de novo) plus the 0.3% non-VCEP threshold exceeded by AFR AF (1.5%) and grpmax FAF (1.4%).

Sources

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗generic_acmg_combination_rulesPMID:25741868 ↗

BP7 SupportingMet (supporting): the variant is synonymous (p.Ile140=) and splice-prediction tools indicate no effect on splicing (SpliceAI max delta 0.13, below the 0.2 threshold), with the change located deep within exon 4, away from splice consensus sites. Details ▾Hide ▴

Reasoning

BP7 is met at supporting strength under generic ACMG/AMP 2015 (PMID:25741868). (1) The variant is synonymous: Mutalyzer normalization NM_001904.4(NP_001895.1):p.(=) and VariantValidator NP_001895.1:p.(Ile140=); gnomAD-Canada VEP annotates most_severe_consequence 'synonymous_variant'. (2) Splicing prediction algorithms predict no impact to the splice consensus sequence nor creation of a new alternate splice site: SpliceAI max delta = 0.13 (DS_AG 0.13, DS_AL 0.0, DS_DG 0.0, DS_DL 0.0; pangolin_SG 0.04), below the 0.2 splice-altering threshold, and the evidence sentence states 'no significant splice impact'. Positional context is consistent: c.420 lies deep in exon 4 (exon 4 spans c.242-c.495 per Mutalyzer selector), ~75 nt from both the intron 3/exon 4 acceptor and the exon 4/intron 4 donor, i.e., outside any splice consensus motif. (3) The 'nucleotide is not highly conserved' prong could NOT be directly verified: no conservation score (phyloP/GERP/phastCons) exists in the workspace artifacts. This prong is flagged for human review; gnomAD population frequency was deliberately NOT used here to infer low conservation, because population-frequency evidence belongs to the population group (BA1/BS1) and must not be double-counted across groups. If the c.420 nucleotide were shown to be highly conserved, BP7 would need to be withdrawn and BP4/PP3 reassessed.

Rule

ACMG/AMP 2015 BP7 (supporting benign): a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new alternate splice site AND the nucleotide is not highly conserved (PMID:25741868). Synonymous and no-splice-impact prongs verified; conservation prong pending human review.

Evidence considered

Synonymous consequence p.(Ile140=) (Mutalyzer NM_001904.4(NP_001895.1):p.(=); VariantValidator NP_001895.1:p.(Ile140=); gnomAD-Canada VEP 'synonymous_variant')
SpliceAI DS_AG 0.13 / DS_AL 0.0 / DS_DG 0.0 / DS_DL 0.0, max delta 0.13 — no splice consensus impact, no new splice site creation above threshold
Mutalyzer exon structure: exon 4 spans c.242-c.495; c.420 is ~75 nt from both intron boundaries (outside splice consensus)
Conservation prong unverified — no phyloP/GERP/phastCons score in bundle (human review flagged)

Still missing

Nucleotide conservation at c.420 (e.g., phyloP/GERP/phastCons) not retrieved — BP7's 'not highly conserved' prong unverified; confirm before finalizing classification
No RNA/splice functional assay (RT-PCR/minigene) for this exact variant exists in the workspace literature

Sources

spliceai ↗PMID:25741868 ↗generic_acmg_combination_rules

Not met · 7 · evaluated, threshold not reached

PS4 Not met: no case-control or variant-specific case data show enrichment of this variant in affected individuals. Instead, it is common in general-population databases (up to about 1.5% in African/African American individuals), which argues against a pathogenic role. Details ▾Hide ▴

Reasoning

PS4 (Richards et al. 2015, PMID:25741868) requires the prevalence of the variant in affected individuals to be significantly increased compared with controls (case-control study). No case-control study, case-series enrichment analysis, or variant-specific case report for CTNNB1 NM_001904.4:c.420T>C (p.Ile140=) is present in the case bundle; the literature packet contains only the ACMG/AMP standards paper (PMID:25741868) and the Sherloc refinement (PMID:28492532), both methodology papers with no variant-specific case data. In contrast, the variant is common in general-population databases (gnomAD v2.1 total AF 0.1827%, 516/282,482 alleles, 8 homozygotes; gnomAD v4.1 total AF 0.0926%, 1,495/1,614,046 alleles, 17 homozygotes; AFR AF 1.5-1.6%), which is inconsistent with a pathogenic-enrichment signal for a rare CTNNB1-related neurodevelopmental disorder, and SpliceAI predicts no significant splice impact (max delta 0.13). PS4 is therefore not met under the governing generic ACMG/AMP 2015 framework.

Rule

PS4: prevalence of variant in affected individuals significantly increased compared with controls (case-control study) - generic ACMG/AMP 2015 (PMID:25741868); no applicable VCEP/CSPEC for CTNNB1

Evidence considered

literature_pass.json: only methodology papers (PMID:25741868 ACMG standards; PMID:28492532 Sherloc), no case-control or case-series data
gnomAD v2.1 total AF 0.001827 (516/282,482 alleles, 8 homozygotes; AFR AF 0.0158) - high population frequency contradicts pathogenic enrichment
gnomAD v4.1 total AF 0.000926 (1,495/1,614,046 alleles, 17 homozygotes; AFR AF 0.0150)
SpliceAI max delta score 0.13 (no predicted splice impact for this synonymous variant)

Still missing

No case-control cohort study for c.420T>C was identified; if one becomes available (cases with CTNNB1-related neurodevelopmental disorder vs controls), it should be evaluated for PS4.

Sources

PMID:25741868 ↗gnomad_v2 ↗gnomad_v4 ↗PMID:28492532 ↗

PM2 Not met: the variant is not rare. It appears in gnomAD at overall frequencies of about 0.09-0.18%, with a maximum population frequency of about 1.5% (African/African American) and multiple homozygotes - consistent with a common polymorphism (rs3856746) rather than a rare disease allele. Details ▾Hide ▴

Reasoning

Generic ACMG/AMP 2015 (Richards et al., PMID:25741868) PM2 requires the variant to be absent from (or below the expected carrier frequency if recessive) a large general population or control cohort (>1000 individuals) that is race-matched to the patient. NM_001904.4:c.420T>C is NOT rare: it is present in gnomAD v2.1 at overall AF 0.183% (516/282,482 alleles, 8 homozygotes), in gnomAD v4.1 at overall AF 0.093% (1,495/1,614,046 alleles, 17 homozygotes), and in gnomAD-Canada v1.0 at AF 0.13% (24/18,420), with maximum population AF (AFR) of 1.50-1.58% across databases. This is far above the non-VCEP house PM2 threshold (AF < 0.1%): although the v4.1 overall AF (0.093%) is nominally below 0.1%, the maximum population AF of ~1.5% and the presence of 17 homozygotes demonstrate the variant is a common population polymorphism (rs3856746), not a rare variant. PM2 is additionally mutually exclusive with the met BA1/BS1 benign frequency criteria (a variant whose frequency supports benignity cannot simultaneously satisfy the rarity-based PM2 criterion). PM2 is not met.

Rule

Generic ACMG/AMP 2015 PM2 (moderate pathogenic): absent from (or below expected carrier frequency if recessive) large race-matched control population; non-VCEP house threshold AF < 0.1% (not met: max population AF ~1.5%).

Evidence considered

gnomAD v2.1: overall AF 0.00182667 (516/282,482, hom 8), AFR AF 0.0157827
gnomAD v4.1: overall AF 0.000926244 (1,495/1,614,046, hom 17), AFR AF 0.0149689
gnomAD-Canada v1.0: AF 0.00130293 (24/18,420)
ACMG/AMP 2015 PM2 definition (PMID:25741868): absence from large race-matched control population
Mutual exclusivity with met BA1/BS1

Still missing

None for PM2 determination: the variant is present at appreciable frequency in all queried population databases (max AFR AF ~1.5%, 17 homozygotes in v4.1), which excludes PM2 regardless of threshold details.

Sources

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗generic_acmg_combination_rulesPMID:25741868 ↗

PP3 Not met: no computational evidence indicates a deleterious effect. SpliceAI predicts no significant splicing impact (max delta 0.13, below the 0.2 threshold), and missense predictors do not apply to a synonymous change. Details ▾Hide ▴

Reasoning

Generic ACMG/AMP 2015 (PMID:25741868) governs: no ClinGen CSPEC, VCEP, or local custom gene framework exists for CTNNB1 in this workspace (cspec found=false; vcep_materials.json gene_vcep_dir=null, framework_mode=generic_acmg, precedence_rank 3). PP3 requires multiple lines of computational evidence supporting a deleterious effect on the gene or gene product. Splice-impact path evaluated: SpliceAI (source_registry key 'spliceai') reports max delta score = 0.13 (DS_AG 0.13, DS_AL 0.0, DS_DG 0.0, DS_DL 0.0; pangolin_SG 0.04), below the 0.2 splice-altering threshold and reported as 'no significant splice impact'; variant_consequence 'sequence_variant'. Missense in-silico path not applicable: the variant is synonymous (NM_001904.4:c.420T>C, NP_001895.1:p.(Ile140=); gnomAD VEP most_severe_consequence 'synonymous_variant'), and REVEL and BayesDel lookups both returned found=false (missense-oriented tools; no score exists for a synonymous change; aGVGD not present in the bundle). No conservation-based or other computational line supports a deleterious effect, so PP3 is not met; the negative SpliceAI result does not support PP3.

Rule

ACMG/AMP 2015 PP3 (supporting pathogenic): multiple lines of computational evidence support a deleterious effect on the gene or gene product (PMID:25741868). Not met: sole applicable computational line (SpliceAI) is negative and the missense path does not apply to a synonymous variant.

Evidence considered

SpliceAI max delta 0.13 (DS_AG 0.13, DS_AL 0.0, DS_DG 0.0, DS_DL 0.0) — no significant splice impact predicted, below 0.2 threshold
Consequence class: synonymous p.(Ile140=) (Mutalyzer/VariantValidator; gnomAD-Canada VEP 'synonymous_variant')
REVEL lookup found=false (missense-only tool, inapplicable to synonymous variant)
BayesDel lookup found=false (missense-only tool, inapplicable to synonymous variant)
aGVGD: not present in evidence bundle

Still missing

No CADD/conservation-based pathogenicity scores retrieved — not required for this negative call, but would be the only remaining computational path if a splice-impact hypothesis ever emerged

Sources

spliceai ↗PMID:25741868 ↗generic_acmg_combination_rules

PP5 Not met: no expert-panel classification labels this variant pathogenic. ClinVar lists it as Benign based on four laboratory submissions - the opposite direction - so PP5 is not met. Details ▾Hide ▴

Reasoning

PP5 (Richards et al. 2015, PMID:25741868) is applied in this group only for an exact-variant ClinVar expert-panel classification of Pathogenic/Likely pathogenic. ClinVar variation 709750 (NM_001904.4(CTNNB1):c.420T>C (p.Ile140=)) carries an aggregate classification of Benign from 4 germline submissions (GeneDx, Labcorp, CeGaT, Breakthrough Genomics), all with review status 'criteria provided, single submitter'; expert_panel_submissions = 0, review stars = 2, expert_panels = {}. No expert-panel classification exists, the label is in the opposite (benign) direction, and ordinary laboratory submissions and aggregate ClinVar labels must never trigger PP5. PP5 is not met.

Rule

PP5: reputable source (expert-panel ClinVar classification) reports variant pathogenic without evidence available for independent evaluation; restricted to exact-variant expert-panel Pathogenic/LP - generic ACMG/AMP 2015 (PMID:25741868)

Evidence considered

ClinVar 709750 aggregate classification 'Benign'; 0 expert-panel submissions; review stars = 2; all 4 submissions single-submitter laboratory assertions
clinvar_submission_audit.json: expert_panel_submissions = 0; usable_for_criterion_leads = 2 (no expert panel leads)

Sources

clinvar ↗PMID:25741868 ↗

BS2 Not met: although homozygotes are present in gnomAD, that database does not provide phenotype-verified healthy-adult carrier status, which BS2 requires. Details ▾Hide ▴

Reasoning

Generic ACMG/AMP 2015 (Richards et al., PMID:25741868) BS2 requires the variant to be observed in a well-documented healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder with full penetrance expected at an early age. gnomAD v2.1 reports 8 homozygotes and gnomAD v4.1 reports 17 homozygotes (15 AFR, 1 MID, 1 remaining) for NM_001904.4:c.420T>C, which is notable because a fully penetrant, early-onset dominant neurodevelopmental disorder allele would not be expected to appear homozygous in a general population cohort; this observation supports benignity and is consistent with the BA1/BS1 determinations. However, gnomAD is a general population database without individual-level phenotype verification, so carriers are not 'well-documented healthy adults' as BS2 requires; the case bundle contains no phenotype-verified healthy-adult carrier observations from any cohort. BS2 is therefore not met on the available evidence. The homozygote observations are already captured under BA1/BS1 and do not require BS2 to be applied.

Rule

Generic ACMG/AMP 2015 BS2 (strong benign): variant observed in a well-documented healthy adult for a fully penetrant early-onset disorder; not met because gnomAD lacks phenotype verification.

Evidence considered

gnomAD v2.1: 8 homozygotes (all AFR), considered but not sufficient for BS2 because gnomAD is not phenotype-verified
gnomAD v4.1: 17 homozygotes (15 AFR, 1 MID, 1 remaining), considered but not sufficient for BS2
gnomAD-Canada v1.0: 0 homozygotes
ACMG/AMP 2015 BS2 definition (PMID:25741868): requires well-documented healthy adult observation

Still missing

Phenotype-verified healthy adult carrier observations (e.g., a case-control or well-phenotyped cohort documenting unaffected adult carriers) would be needed to apply BS2; gnomAD homozygote counts alone do not satisfy the 'well-documented healthy adult' requirement.

Sources

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗generic_acmg_combination_rulesPMID:25741868 ↗

BP4 Not met: BP4 requires multiple independent computational lines predicting no impact. Only the SpliceAI no-impact prediction is available, and it is already used for BP7, so applying it again would double-count a single line of evidence. Details ▾Hide ▴

Reasoning

Generic ACMG/AMP 2015 BP4 (PMID:25741868) requires MULTIPLE lines of computational evidence suggesting no impact on the gene or gene product (conservation, evolutionary, splicing impact, etc.). Only a single computational line is available: SpliceAI predicts no significant splice impact (max delta 0.13 < 0.2; DS_AG 0.13, DS_AL 0.0, DS_DG 0.0, DS_DL 0.0). The four SpliceAI sub-scores are outputs of one predictor and cannot be counted as separate lines. REVEL/BayesDel are not applicable (synonymous variant; both lookups found=false) and no conservation score (phyloP/GERP/phastCons) was retrieved. The same SpliceAI no-impact prediction is the evidence for BP7 (the more specific criterion for synonymous variants); applying it again to BP4 would double-count one prediction across two criteria, which the group guidance prohibits. BP4 is therefore not independently met.

Rule

ACMG/AMP 2015 BP4 (supporting benign): multiple lines of computational evidence suggest no impact on the gene or gene product (PMID:25741868). Not independently met: only one computational line available; same prediction already applied to BP7.

Evidence considered

SpliceAI max delta 0.13 — single computational line; direction (no impact) is correct but multiplicity is insufficient for BP4
No conservation score (phyloP/GERP/phastCons) retrieved in workspace artifacts
REVEL/BayesDel found=false — missense-only tools, inapplicable to synonymous variant
SpliceAI no-impact evidence routed to BP7 (more specific criterion for synonymous variants) to avoid double-counting

Still missing

A second independent computational line (e.g., a conservation score such as phyloP/GERP or a second splice predictor such as VarSeak/MaxEntScan) would be required to satisfy BP4's 'multiple lines' requirement without double-counting the single SpliceAI prediction

Sources

spliceai ↗PMID:25741868 ↗generic_acmg_combination_rules

BP6 Not met: BP6 requires an expert-panel benign classification for this exact variant. Only ordinary laboratory submissions are available, which do not meet the criterion. Details ▾Hide ▴

Reasoning

BP6 (Richards et al. 2015, PMID:25741868) is applied in this group only for an exact-variant ClinVar expert-panel classification of Benign/Likely benign. ClinVar variation 709750 is labeled Benign, but that label derives from 4 ordinary laboratory submissions (all 'criteria provided, single submitter'; expert_panel_submissions = 0; review stars = 2; expert_panels = {}). Per group policy, ordinary laboratory submissions, aggregate ClinVar labels, and non-expert assertions must never trigger BP6; only an exact-variant expert-panel Benign/LB classification would. No such classification exists, so BP6 is not met. The benign laboratory consensus is not repurposed as BP6 evidence here.

Rule

BP6: reputable source (expert-panel ClinVar classification) reports variant benign without evidence available for independent evaluation; restricted to exact-variant expert-panel Benign/LB - generic ACMG/AMP 2015 (PMID:25741868)

Evidence considered

ClinVar 709750: aggregate 'Benign' from 3 clinical laboratories (4 submissions); 0 expert-panel submissions; review stars = 2
clinvar_submission_audit.json: expert_panel_submissions = 0

Sources

clinvar ↗PMID:25741868 ↗

Not assessed · 9 · no assessment recorded

PS2 Not assessed: insufficient evidence was available. No proband or parental (maternity and paternity) genotype data were available to determine whether the variant arose de novo. Details ▾Hide ▴

Reasoning

PS2 (de novo, maternity and paternity confirmed) cannot be assessed: the case bundle contains no proband-level genotype or parental testing data for NM_001904.4:c.420T>C (CTNNB1, p.(Ile140=), synonymous). None of the four ClinVar submissions (SCV001960318 GeneDx, SCV001024373 Labcorp/Invitae, SCV003916437 CeGaT, SCV005238821 Breakthrough Genomics) report any criteria signals (evidence_signals.criteria_found is empty for all), and the only two PMIDs (25741868 ACMG/AMP guideline; 28492532 Sherloc) are methodology papers that do not mention the variant. No source in the bundle reports that the variant arose de novo or that either parent tested negative. Framework: generic ACMG/AMP 2015 fallback (no ClinGen CSPEC, no CTNNB1 VCEP).

Rule

ACMG/AMP 2015 (Richards et al., PMID:25741868) PS2: De novo (maternity and paternity confirmed) - variant observed to have arisen de novo with both parental samples shown by identity testing to be the biological parents; phenotype must match the gene's disease association with reasonable specificity

Evidence considered

clinvar (VCV000709750 submissions audit: no segregation/de novo criteria signals)
PMID:25741868 (rule definition consulted; no variant-specific evidence)
PMID:28492532 (background framework; no variant-specific evidence)

Still missing

No proband de novo testing data: parental genotypes (and identity/parentage confirmation) for any proband carrying c.420T>C are not present in the case bundle
No phenotype-consistency assessment possible: no proband phenotype described in the bundle to compare against CTNNB1-associated phenotypes
No variant-specific case literature: neither PMID:25741868 nor PMID:28492532 mentions the variant

Sources

PMID:25741868 ↗PMID:28492532 ↗

PS3 Not assessed: insufficient evidence was available; no functional assay results could be evaluated for this variant. Details ▾Hide ▴

Reasoning

PS3 could not be assessed because its agent did not produce valid output.

Still missing

attempt 1: evidence_refs must contain only source_registry keys
attempt 2: evidence_refs must contain only source_registry keys
attempt 3: evidence_refs must contain only source_registry keys

PM6 Not assessed: insufficient evidence was available; no parental testing data were available to support an assumed de novo occurrence. Details ▾Hide ▴

Reasoning

PM6 (assumed de novo, without confirmation of paternity and maternity) cannot be assessed for the same reason as PS2: there is no proband or parental testing information of any kind in the case bundle for NM_001904.4:c.420T>C. No source reports an assumed de novo occurrence, no parental sample results (confirmed or unconfirmed) are available, and neither retrieved publication mentions the variant. The ClinVar record (VCV000709750) is Benign with 3 clinical laboratories but contains no criterion-level assertions. Generic ACMG/AMP 2015 fallback applies (no CSPEC/VCEP).

Rule

ACMG/AMP 2015 (Richards et al., PMID:25741868) PM6: Assumed de novo, but without confirmation of paternity and maternity

Evidence considered

clinvar (VCV000709750: no de novo/assumed-de-novo assertions)
PMID:25741868 (rule definition consulted; no variant-specific evidence)
PMID:28492532 (background framework; no variant-specific evidence)

Still missing

No proband genotype data and no parental test results (even unconfirmed) to support an assumed de novo occurrence
No indication of germline mosaicism or affected-sibling pattern relevant to PM6
No case-level publication reporting the variant in a proband

Sources

PMID:25741868 ↗PMID:28492532 ↗

PP1 Not assessed: insufficient evidence was available; no family genotyping or segregation data were reported. Absence of data is not evidence for or against segregation. Details ▾Hide ▴

Reasoning

PP1 (co-segregation with disease in affected family members in a gene definitively known to cause the disease) cannot be assessed: the case bundle contains no family/segregation data whatsoever. There are no affected family members genotyped, no meiosis/segregation counts, and no pedigrees reported in any source. The two retrieved PMIDs (25741868, 28492532) are methodology papers with no variant mention, and the ClinVar submissions report no segregation assertions. Absence of segregation data is not evidence for or against segregation. Generic ACMG/AMP 2015 fallback applies (no CSPEC/VCEP).

Rule

ACMG/AMP 2015 (Richards et al., PMID:25741868) PP1: Co-segregation with disease in affected family members in multiple affected family members in a gene definitively known to cause the disease

Evidence considered

clinvar (VCV000709750: no segregation assertions)
PMID:25741868 (rule definition consulted; no variant-specific evidence)
PMID:28492532 (background framework; no variant-specific evidence)

Still missing

No family segregation data: no genotyped affected relatives, no meiosis counts, no pedigree information for any carrier of c.420T>C
No CTNNB1 VCEP segregation-scoring thresholds available (generic PP1 rule would apply if data existed)

Sources

PMID:25741868 ↗PMID:28492532 ↗

PP4 Not assessed: insufficient evidence was available; no phenotype description or family history was available to evaluate whether the variant fits a CTNNB1-related presentation. Details ▾Hide ▴

Reasoning

PP4 (Richards et al. 2015, PMID:25741868) requires the variant to be found in a case with a phenotype or family history highly specific for a disease with a single genetic etiology (here CTNNB1-related neurodevelopmental disorder). The case bundle contains no proband phenotype description, clinical indication, or family history data - only variant-centric database evidence. Because the phenotype cannot be evaluated at all, PP4 cannot be assessed; the synonymous consequence of the variant does not substitute for phenotype data.

Rule

PP4: variant found in a case with phenotype or family history highly specific for a disease with a single genetic etiology - generic ACMG/AMP 2015 (PMID:25741868)

Evidence considered

Case bundle (review_manifest.json, case_summary.json) contains no proband phenotype data

Still missing

No proband phenotype or family history information in the case bundle; PP4 requires evidence that the patient's phenotype is highly specific for CTNNB1-related disorder.

Sources

PMID:25741868 ↗

BS3 Not assessed: insufficient evidence was available; no well-established functional studies showing no damaging effect could be evaluated. Details ▾Hide ▴

Reasoning

BS3 could not be assessed because its agent did not produce valid output.

Still missing

attempt 1: evidence_refs must contain only source_registry keys
attempt 2: evidence_refs must contain only source_registry keys
attempt 3: evidence_refs must contain only source_registry keys

BS4 Not assessed: insufficient evidence was available; no family members were genotyped, so lack of segregation could not be demonstrated. Details ▾Hide ▴

Reasoning

BS4 (lack of segregation in affected family members) cannot be assessed: no affected or unaffected family members were genotyped in any source in the case bundle, so there is no evidence that the variant is present in unaffected relatives or absent in affected relatives. The high population frequency of this synonymous variant (gnomAD v4.1 total AF 0.000926, AFR AF 0.01497, 17 homozygotes) is relevant to BA1/BS1 and is adjudicated by the population frequency group, not this group. Absence of segregation data must not be converted into a benign non-segregation finding. Generic ACMG/AMP 2015 fallback applies (no CSPEC/VCEP).

Rule

ACMG/AMP 2015 (Richards et al., PMID:25741868) BS4: Lack of segregation in affected family members

Evidence considered

clinvar (VCV000709750: no family/segregation assertions)
PMID:25741868 (rule definition consulted; no variant-specific evidence)
PMID:28492532 (background framework; no variant-specific evidence)

Still missing

No genotyped affected or unaffected family members - non-segregation (variant present in affected individual(s) or absent in unaffected relative(s)) cannot be demonstrated
No family studies in the retrieved literature (both PMIDs are methodology papers without variant mention)

Sources

PMID:25741868 ↗PMID:28492532 ↗

BP2 Not assessed: insufficient evidence was available; no phase (trans/cis) or co-occurrence observations with a pathogenic variant were reported. Details ▾Hide ▴

Reasoning

BP2 (Richards et al. 2015, PMID:25741868) is an observation-based benign-supporting criterion: 'Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder; or observed in cis with a pathogenic variant in any inheritance pattern'. The consolidated evidence bundle contains no proband phenotype data and no family genotype data: all four ClinVar submissions (GeneDx, Labcorp, CeGaT, Breakthrough Genomics) are single-submitter Benign calls with condition labels 'not provided'/empty, no segregation data, no co-occurrence observations, and no phase (trans/cis) information; prefetch/evidence/literature passes surfaced no familial or phase evidence either. Because the required positive observation (this variant in trans with a pathogenic variant, or in cis with a pathogenic variant) is entirely absent from the evidence base, BP2 cannot be evaluated and is returned as not_assessed. Gap: phase/family/co-occurrence data would be required. Context only (not determinative here): c.420T>C is a common synonymous variant in gnomAD (v2.1 total AF 0.183%, 8 homozygotes; v4.1 total AF 0.093%, 17 homozygotes) and is Benign in ClinVar (3 clinical labs), which other criteria groups evaluate via population-frequency/benign criteria; these data supply no phase information for BP2.

Rule

BP2 (Richards et al. 2015): Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder; or observed in cis with a pathogenic variant in any inheritance pattern.

Evidence considered

Rule text: BP2 requires observation in trans with a pathogenic variant (fully penetrant dominant disorder) or in cis with a pathogenic variant (Richards et al. 2015, PMID:25741868)
ClinVar record VCV000709750: 4 submissions, all Benign, no conditions listed, no phase/co-occurrence data (SCV001960318, SCV001024373, SCV003916437, SCV005238821)
Inheritance context: CTNNB1 germline disease is autosomal dominant per pvs1_gene_context, so the 'trans with pathogenic variant for fully penetrant dominant disorder' prong would require phase data that are absent
No family segregation or proband observations surfaced in prefetch.json, evidence.json, or literature_pass.json

Still missing

No proband/family genotype or phase (trans/cis) data in the case bundle; no observation of c.420T>C co-occurring with a pathogenic CTNNB1 variant
ClinVar submissions provide no segregation or co-occurrence observations (conditions 'not provided'/empty), so no affected-proband allelic evidence is available

Sources

PMID:25741868 ↗generic_acmg_combination_rulespvs1_gene_contextclinvar ↗

BP5 Not assessed: insufficient evidence was available; no alternate molecular basis of disease (for example, a co-occurring pathogenic variant) was reported for the case. Details ▾Hide ▴

Reasoning

BP5 (Richards et al. 2015, PMID:25741868) requires the variant to be found in a case with an alternate molecular basis for disease (e.g., a different pathogenic variant in the same gene or in another gene that explains the phenotype). The case bundle contains no proband genotype or phenotype data - no co-occurring variant calls, no second variant in CTNNB1 or elsewhere, and no clinical case context are available. BP5 therefore cannot be assessed.

Rule

BP5: variant found in a case with an alternate molecular basis for disease - generic ACMG/AMP 2015 (PMID:25741868)

Evidence considered

Case bundle contains no proband-level genotype or phenotype information

Still missing

No proband genotype/phenotype data to determine whether an alternate molecular basis for disease exists (no co-occurring variants or clinical case context in the bundle).

Sources

PMID:25741868 ↗

Not applicable · 9· recorded as not applicable Show reasons ▾Hide reasons ▴

PVS1 N/ANot applicable: this is a synonymous (silent) change that leaves the protein sequence unchanged (p.Ile140=). PVS1 requires a null variant such as a stop, frameshift, or splice-site disruption that would trigger nonsense-mediated decay or abolish protein function, so it does not apply. Details ▾Hide ▴

Reasoning

PVS1 (ClinGen SVI PVS1 recommendations, PMC6185798, pvs1_generic_framework) applies only to null variant classes — nonsense, frameshift, canonical ±1/2 splice-consensus, translation-initiation-codon loss, and stop-loss variants — each expected to trigger nonsense-mediated decay or otherwise abolish normal protein function. NM_001904.4:c.420T>C in CTNNB1 is a synonymous (silent) substitution predicted to produce NP_001895.1:p.(Ile140=). As a result, no null-variant mechanism (nonsense-mediated decay, truncation, or canonical splice disruption) is triggered by this variant class, so PVS1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.

Rule

deterministic_prefilter: requires_null_variant_class

Evidence considered

Deterministic consequence classification: synonymous (prefetch.json normalized protein consequence)

Sources

pvs1_generic_framework ↗generic_acmg_combination_rules

PS1 N/ANot applicable: PS1 compares the amino acid change to a previously established pathogenic variant at the same residue. Because this variant does not change the amino acid (p.Ile140=), there is no altered residue to compare. Details ▾Hide ▴

Reasoning

PS1 (Richards et al. 2015, PMID:25741868) requires the same amino acid change as a previously established pathogenic variant, evaluated regardless of the underlying nucleotide change. NM_001904.4:c.420T>C in CTNNB1 is a synonymous (silent) substitution predicted to produce NP_001895.1:p.(Ile140=). As a result, no altered amino acid exists at this position to compare against any previously established pathogenic missense variant, so PS1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.

Rule

deterministic_prefilter: requires_missense

Evidence considered

Deterministic consequence classification: synonymous (prefetch.json normalized protein consequence)

Sources

generic_acmg_combination_rules

PM1 N/ANot applicable: PM1 concerns missense variants in mutational hotspots or critical functional domains. This synonymous change alters no amino acid, so there is no altered residue to evaluate. Details ▾Hide ▴

Reasoning

PM1 (Richards et al. 2015, PMID:25741868) applies to a missense variant located in a mutational hot spot and/or a critical, well-established functional domain without benign variation. NM_001904.4:c.420T>C in CTNNB1 is a synonymous (silent) substitution predicted to produce NP_001895.1:p.(Ile140=). As a result, no altered residue exists to evaluate for mutational hot-spot or critical-domain membership, so PM1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.

Rule

deterministic_prefilter: requires_missense

Evidence considered

Deterministic consequence classification: synonymous (prefetch.json normalized protein consequence)

Sources

generic_acmg_combination_rules

PM3 N/ANot applicable: PM3 applies only to recessive disorders. CTNNB1 syndrome is an autosomal dominant neurodevelopmental disorder, so this criterion does not apply. Details ▾Hide ▴

Reasoning

PM3 (Richards et al. 2015, PMID:25741868) applies only 'for recessive disorders, detected in trans with a pathogenic variant'. CTNNB1 germline disease (CTNNB1 syndrome / neurodevelopmental disorder with spastic diplegia and visual defects, MIM 615075) is an autosomal dominant disorder caused by heterozygous, largely de novo loss-of-function or activating variants, as established by the gene-level literature review in pvs1_gene_context (supporting sources incl. PMID:36083290, PMID:33350591, PMID:41082542). No recessive CTNNB1 germline phenotype is established in the evidence bundle, so the structural prerequisite of PM3 (a recessive disorder) is not met regardless of variant data. Additionally, no proband/family genotype or second-variant (trans-phase) observation exists anywhere in the bundle, so even the trans-observation component could not be evaluated. PM3 is therefore not applicable to this autosomal dominant gene-disorder context. Determination made under the generic ACMG/AMP 2015 fallback (framework_mode=generic_acmg; no CSPEC/VCEP or local custom framework for CTNNB1).

Rule

PM3 (Richards et al. 2015): For recessive disorders, detected in trans with a pathogenic variant.

Evidence considered

Rule prerequisite: PM3 requires a recessive disorder (Richards et al. 2015, PMID:25741868)
Inheritance mode: CTNNB1 germline phenotypes are autosomal dominant per pvs1_gene_context gene-level literature review (supporting sources incl. PMID:36083290, PMID:33350591, PMID:41082542)
Absence of trans-phase data: no second CTNNB1 variant or family genotype observations in the bundle (ClinVar submissions SCV001960318, SCV001024373, SCV003916437, SCV005238821 report no conditions and no co-occurrence data)

Sources

PMID:25741868 ↗generic_acmg_combination_rulespvs1_gene_contextclinvar ↗

PM4 N/ANot applicable: PM4 applies to changes in protein length (in-frame insertions/deletions or stop-loss). This synonymous variant leaves the protein length unchanged. Details ▾Hide ▴

Reasoning

PM4 (Richards et al. 2015, PMID:25741868) applies to protein length changes: in-frame insertions/deletions in a non-repetitive region, or stop-loss variants that extend the protein past the reference stop codon. NM_001904.4:c.420T>C in CTNNB1 is a synonymous (silent) substitution predicted to produce NP_001895.1:p.(Ile140=). As a result, no change in protein length occurs, so there is nothing for this criterion to evaluate, so PM4's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.

Rule

deterministic_prefilter: requires_stop_loss_or_nonrepeat_indel

Evidence considered

Deterministic consequence classification: synonymous (prefetch.json normalized protein consequence)

Sources

pvs1_generic_framework ↗generic_acmg_combination_rules

PM5 N/ANot applicable: PM5 requires a novel missense change at a residue where a different missense change is already pathogenic. This variant changes no amino acid. Details ▾Hide ▴

Reasoning

PM5 (Richards et al. 2015, PMID:25741868) requires a novel missense change at an amino acid residue where a different missense change has previously been determined to be pathogenic. NM_001904.4:c.420T>C in CTNNB1 is a synonymous (silent) substitution predicted to produce NP_001895.1:p.(Ile140=). As a result, no missense change exists at this residue to compare against a different pathogenic missense change at the same position, so PM5's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.

Rule

deterministic_prefilter: requires_missense

Evidence considered

Deterministic consequence classification: synonymous (prefetch.json normalized protein consequence)

Sources

generic_acmg_combination_rules

PP2 N/ANot applicable: PP2 concerns missense variants in genes with a low rate of benign missense variation. This is a synonymous change, so the criterion does not apply. Details ▾Hide ▴

Reasoning

PP2 (Richards et al. 2015, PMID:25741868) applies to a missense variant in a gene with a low rate of benign missense variation, where missense variants are a common mechanism of disease. NM_001904.4:c.420T>C in CTNNB1 is a synonymous (silent) substitution predicted to produce NP_001895.1:p.(Ile140=). As a result, the gene's missense-constraint properties are irrelevant because no missense change is present to evaluate, so PP2's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.

Rule

deterministic_prefilter: requires_missense

Evidence considered

Deterministic consequence classification: synonymous (prefetch.json normalized protein consequence)

Sources

generic_acmg_combination_rules

BP1 N/ANot applicable: BP1 applies to missense variants in genes where truncating variants cause disease. This is a synonymous change, so the criterion does not apply. Details ▾Hide ▴

Reasoning

BP1 (Richards et al. 2015, PMID:25741868) applies to a missense variant in a gene for which primarily truncating variants are known to cause disease. NM_001904.4:c.420T>C in CTNNB1 is a synonymous (silent) substitution predicted to produce NP_001895.1:p.(Ile140=). As a result, the gene's truncating-variant mechanism is irrelevant because no missense change is present to evaluate, so BP1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.

Rule

deterministic_prefilter: requires_missense

Evidence considered

Deterministic consequence classification: synonymous (prefetch.json normalized protein consequence)

Sources

generic_acmg_combination_rules

BP3 N/ANot applicable: BP3 applies to in-frame insertions or deletions in repetitive regions. This synonymous variant does not alter protein length. Details ▾Hide ▴

Reasoning

BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_001904.4:c.420T>C in CTNNB1 is a synonymous (silent) substitution predicted to produce NP_001895.1:p.(Ile140=). As a result, the variant does not alter protein length within a repeat region, so there is nothing for this criterion to evaluate, so BP3's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.

Rule

deterministic_prefilter: requires_repeat_region_indel

Evidence considered

Deterministic consequence classification: synonymous (prefetch.json normalized protein consequence)

Sources

pvs1_generic_framework ↗generic_acmg_combination_rules

Identifiers

Gene: CTNNB1
Transcript: NM_001904.4
Coding (HGVS c.): NM_001904.4:c.420T>C
Protein (HGVS p.): NP_001895.1:p.(Ile140=)
GRCh38: chr3:41225132 T>C
GRCh37: chr3:41266623 T>C
ClinVar: 709750
COSMIC: COSV104442201

Gene diagram

Every interpreted variant in CTNNB1, mapped onto the exon structure of NM_001904.4. Select a row to find it on the plot.

CTNNB1NM_001904.4

Fetching transcript structure from UCSC…

Exons

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Transcript span

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Strand

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Variants mapped

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Source

UCSC ncbiRefSeqCurated

All variants in CTNNB1 — Select a row to find it on the plot; use the link to open its page.

	Protein	Location	Classification	Link

gnomAD v4.1 1,495 / 1,614,046 alleles AF 0.000926 · 17 homozygotes · FAF 0.0142

gnomAD v2.1 516 / 282,482 alleles AF 0.00183 · 8 homozygotes · FAF 0.015

gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 0.00093 · 1495 / 1,614,046 alleles · 17 hom · FAF 0.014

African/African American1123 / 75,022	0.01515 hom
Middle Eastern20 / 6,062	0.00331 hom
Ashkenazi Jewish49 / 29,606	0.0017
Admixed American98 / 59,974	0.0016
Remaining individuals78 / 62,502	0.00121 hom
European (non-Finnish)119 / 1,179,986	0.0001
European (Finnish)5 / 64,020	7.8e-05
South Asian3 / 91,084	3.3e-05

0 alternate alleles recorded in 2 other groups: Amish, East Asian.

gnomAD v2.1

AF 0.0018 · 516 / 282,482 alleles · 8 hom · FAF 0.015

African/African American394 / 24,964	0.0168 hom
Ashkenazi Jewish21 / 10,360	0.002
Remaining individuals14 / 7,220	0.0019
Admixed American52 / 35,352	0.0015
European (non-Finnish)32 / 128,914	0.00025
European (Finnish)2 / 25,112	8e-05
South Asian1 / 30,616	3.3e-05

0 alternate alleles recorded in 1 other group: East Asian.

gnomAD-Canada

AF not recorded · ? / ? alleles

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 0.000926244; MAF= 0.09262%, 1495/1614046 alleles, homozygotes = 17) and has highest observed frequency in the African/African American population (AF= 0.0149689; MAF= 1.49689%, 1123/75022 alleles, homozygotes = 15); grpmax FAF= 0.0142419.

gnomAD v2.1

gnomAD-Canada

This variant is present in gnomAD-Canada v1.0 (AF= 0.0013029315960912053, 24/18420 alleles, homozygotes = 0).

Open the gnomAD-Canada detail page →

SpliceAI and Pangolin

SpliceAI acceptor lossat +11 bp

0.000

SpliceAI acceptor gainat -29 bp

0.130

SpliceAI donor lossat +426 bp

0.000

SpliceAI donor gainat +300 bp

0.000

Pangolin splice lossmagnitude shown

-0.000

Pangolin splice gain

0.040

Other predictors

REVEL: Not available
BayesDel: Not available

How the predictions were used

Reasoning

Rule

ACMG/AMP 2015 BP7 (supporting benign): a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new alternate splice site AND the nucleotide is not highly conserved (PMID:25741868). Synonymous and no-splice-impact prongs verified; conservation prong pending human review.

Evidence considered

Synonymous consequence p.(Ile140=) (Mutalyzer NM_001904.4(NP_001895.1):p.(=); VariantValidator NP_001895.1:p.(Ile140=); gnomAD-Canada VEP 'synonymous_variant')
SpliceAI DS_AG 0.13 / DS_AL 0.0 / DS_DG 0.0 / DS_DL 0.0, max delta 0.13 — no splice consensus impact, no new splice site creation above threshold
Mutalyzer exon structure: exon 4 spans c.242-c.495; c.420 is ~75 nt from both intron boundaries (outside splice consensus)
Conservation prong unverified — no phyloP/GERP/phastCons score in bundle (human review flagged)

Still missing

Nucleotide conservation at c.420 (e.g., phyloP/GERP/phastCons) not retrieved — BP7's 'not highly conserved' prong unverified; confirm before finalizing classification
No RNA/splice functional assay (RT-PCR/minigene) for this exact variant exists in the workspace literature

Sources

spliceai ↗PMID:25741868 ↗generic_acmg_combination_rules

Reasoning

Rule

ACMG/AMP 2015 PP3 (supporting pathogenic): multiple lines of computational evidence support a deleterious effect on the gene or gene product (PMID:25741868). Not met: sole applicable computational line (SpliceAI) is negative and the missense path does not apply to a synonymous variant.

Evidence considered

SpliceAI max delta 0.13 (DS_AG 0.13, DS_AL 0.0, DS_DG 0.0, DS_DL 0.0) — no significant splice impact predicted, below 0.2 threshold
Consequence class: synonymous p.(Ile140=) (Mutalyzer/VariantValidator; gnomAD-Canada VEP 'synonymous_variant')
REVEL lookup found=false (missense-only tool, inapplicable to synonymous variant)
BayesDel lookup found=false (missense-only tool, inapplicable to synonymous variant)
aGVGD: not present in evidence bundle

Still missing

No CADD/conservation-based pathogenicity scores retrieved — not required for this negative call, but would be the only remaining computational path if a splice-impact hypothesis ever emerged

Sources

spliceai ↗PMID:25741868 ↗generic_acmg_combination_rules

Reasoning

Rule

ACMG/AMP 2015 BP4 (supporting benign): multiple lines of computational evidence suggest no impact on the gene or gene product (PMID:25741868). Not independently met: only one computational line available; same prediction already applied to BP7.

Evidence considered

SpliceAI max delta 0.13 — single computational line; direction (no impact) is correct but multiplicity is insufficient for BP4
No conservation score (phyloP/GERP/phastCons) retrieved in workspace artifacts
REVEL/BayesDel found=false — missense-only tools, inapplicable to synonymous variant
SpliceAI no-impact evidence routed to BP7 (more specific criterion for synonymous variants) to avoid double-counting

Still missing

A second independent computational line (e.g., a conservation score such as phyloP/GERP or a second splice predictor such as VarSeak/MaxEntScan) would be required to satisfy BP4's 'multiple lines' requirement without double-counting the single SpliceAI prediction

Sources

spliceai ↗PMID:25741868 ↗generic_acmg_combination_rules

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.13).

2 paper records listed. 1 cited in the classification. None of the listed paper records explicitly indicates that the variant is named.

Cited in the classification

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S et al. · 2015 May

ACMG/AMP 2015 consensus guidelines (Richards et al.). Consulted solely to establish the rule definitions for the de novo criteria (PS2/PM6) and co-segregation criterion (PP1) under the generic ACMG fallback. The paper contains no variant-specific data: NM_001904.4:c.420T>C / p.(Ile140=) is not mentioned. The extracted full text is partial (~40KB single-line extraction) and includes the Table 3 de novo criteria text but not the BS4 definition from Table 4.
→ BA1 → BS1 → BP7 · supporting Does not name this variant
PMID 25741868 ↗
Source detail

A variant observed to have arisen de novo (parental samples test negative), is considered strong support for pathogenicity if the following conditions are met: Both parental samples were shown through identity testing to be the biological parents of the patient. Note: PM6 applies if identity is assumed but not confirmed.

Location Table 3 (Pathogenic criteria), 'PS2 PM6 De novo variants' section; partial full-text extraction (publications/25741868.txt, chars ~29768-30062)

Context Methodology/consensus guideline (ACMG/AMP/CAP workgroup), not a cohort or case study; used only for criterion rule definitions in generic ACMG fallback mode.

Other recorded publications

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K et al. · 2017

Sherloc (Nykamp et al., 2017): a refinement of the ACMG-AMP criteria framework, retrieved as background review via the Labcorp/Invitae ClinVar submission. Consulted only for framework context for this group; no full text is available in the case bundle and the paper does not mention NM_001904.4:c.420T>C or p.(Ile140=). It provides no de novo or segregation evidence for this variant.
Does not name this variant
PMID 28492532 ↗
Quoted passage
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
Metadata/abstract only - no full text in case bundle (fulltext_map.json contains only 25741868)

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 1,495 / 1,614,046 recorded alleles Open source ↗

gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗

SpliceAI Lookup Recorded maximum delta 0.130 Open source ↗

ClinVar 3 Benign Open source ↗

COSMIC Captured COSMIC source record Open source ↗

Cancer hotspots Captured Cancer Hotspots source record Open source ↗

OncoKB Captured OncoKB source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

gnomAD v2.1

gnomAD-Canada

This variant is present in gnomAD-Canada v1.0 (AF= 0.0013029315960912053, 24/18420 alleles, homozygotes = 0).

ClinVar

This variant has been reported in ClinVar as Benign (3 clinical laboratories). (ClinVarID = 709750)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.13).

Functional

OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

Somatic

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV104442201, n = 3 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.