About CTNNB1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
CTNNB1 c.802G>T, p.(Gly268Ter)
Classification
Likely pathogenic
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.
Likely pathogenic.A likely pathogenic classification under the recorded framework.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
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: 2
Benign evidence criteria: 0
Pathogenic criteria applied · 2
PVS1Very strong
PVS1 · very strong
NM_001904.4:c.802G>T is a nonsense variant in exon 6 of 15 exons, predicted to result in a premature termination codon (NP_001895.1:p.Gly268Ter) and trigger nonsense-mediated decay (stop codon >50 nt upstream of the last exon-exon junction). CTNNB1 loss-of-function is an established disease mechanism for autosomal dominant neurodevelopmental disorder with spastic diplegia and visual defects (NEDSDV; MIM 615075), supported by ClinGen haploinsufficiency score of 3 and multiple clinical publications describing germline nonsense and frameshift variants as pathogenic. Per the ClinGen SVI PVS1 decision tree (PMC6185798), a nonsense variant in a gene with an established LoF mechanism where NMD is predicted qualifies for PVS1 at very strong strength.
PM2Moderate
PM2 · moderate
NM_001904.4:c.802G>T is completely absent from large population databases. It is absent from gnomAD v2.1 (0 alleles), gnomAD v4.1 (0 alleles across >140,000 individuals), and gnomAD-Canada v1.0 (0 alleles). Under generic ACMG/AMP non-VCEP cutoffs, absence from population databases supports PM2 at moderate strength.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Likely pathogenic
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PVS1 very strong, PM2 moderate; combination = 1 very strong + 1 moderate, which maps to Likely Pathogenic.
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
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
SpliceAI score
0.020 maximum delta
Recorded SpliceAI maximum delta score: 0.020. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
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
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
29 criteria with recorded statuses: 2 met · 6 not met · 11 not assessed · 10 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_001904.4:c.802G>T (NP_001895.1:p.Gly268Ter) is a nonsense variant in exon 6 of 15 exons in CTNNB1, predicted to result in premature protein termination and nonsense-mediated decay of the transcript.
CTNNB1 loss-of-function is an established disease mechanism for autosomal dominant neurodevelopmental disorder with spastic diplegia and visual defects (NEDSDV; MIM 615075), supported by ClinGen haploinsufficiency score of 3 and multiple publications describing pathogenic germline nonsense and frameshift variants.
This variant is absent from gnomAD v2.1 and v4.1 (0 alleles across >140,000 individuals) and absent from gnomAD-Canada v1.0, consistent with a rare pathogenic variant under strong purifying selection.
The variant is not present in ClinVar, and no functional studies, cosegregation data, or detailed clinical phenotypes for individuals carrying this variant were available in the evidence record.
Applying the generic ACMG/AMP 2015 classification framework (Richards et al. 2015, PMID:25741868), the combination of one very strong criterion (PVS1) and one moderate criterion (PM2) meets the threshold for Likely Pathogenic (1 Very Strong + 1 Moderate).
No criteria match.
Met · 2
PVS1 Very strongNM_001904.4:c.802G>T is a nonsense variant in exon 6 of 15 exons, predicted to result in a premature termination codon (NP_001895.1:p.Gly268Ter) and trigger nonsense-mediated decay (stop codon >50 nt upstream of the last exon-exon junction). CTNNB1 loss-of-function is an established disease mechanism for autosomal dominant neurodevelopmental disorder with spastic diplegia and visual defects (NEDSDV; MIM 615075), supported by ClinGen haploinsufficiency score of 3 and multiple clinical publications describing germline nonsense and frameshift variants as pathogenic. Per the ClinGen SVI PVS1 decision tree (PMC6185798), a nonsense variant in a gene with an established LoF mechanism where NMD is predicted qualifies for PVS1 at very strong strength. Details ▾Hide ▴
Evidence considered
- Nonsense variant NM_001904.4:c.802G>T (NP_001895.1:p.Gly268Ter) in exon 6 of 15 exons
- >50 nt upstream of last exon-exon junction — NMD predicted
- CTNNB1 loss-of-function is an established germline disease mechanism for autosomal dominant NEDSDV (MIM 615075)
- supported by ClinGen haploinsufficiency score of 3
- Multiple publications confirm germline CTNNB1 nonsense/frameshift variants as pathogenic (PMID:41082542
- PMID:36153650
- PMID:36083290)
- ClinGen SVI PVS1 framework (PMC6185798) supports PVS1 at very strong for nonsense variants in LoF-established genes with predicted NMD
Sources
pvs1_generic_framework ↗pvs1_gene_contextpvs1_variant_assessment4108254236153650360832903335059141062690
PM2 ModerateNM_001904.4:c.802G>T is completely absent from large population databases. It is absent from gnomAD v2.1 (0 alleles), gnomAD v4.1 (0 alleles across >140,000 individuals), and gnomAD-Canada v1.0 (0 alleles). Under generic ACMG/AMP non-VCEP cutoffs, absence from population databases supports PM2 at moderate strength. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (0 alleles across all populations)
- Absent from gnomAD v4.1 (0 alleles across >140
- 000 individuals)
- Absent from gnomAD-Canada v1.0 (0 alleles)
Sources
Not met · 6 · evaluated, threshold not reached
PM1 The variant does not lie in a known mutational hotspot or critical functional domain. Cancerhotspots.org shows residue G268 is not a statistically significant hotspot. COSMIC has no entries for this variant. No germline mutational hotspot has been established for CTNNB1 exon 6 by a ClinGen VCEP. Details ▾Hide ▴
Evidence considered
- Cancerhotspots.org: residue G268 not a statistically significant hotspot
- COSMIC: no entries for this variant
PP3 Multiple lines of computational evidence supporting a deleterious effect are not available. REVEL score is unavailable for this variant. BayesDel score of 0.66 provides a single in silico predictor in the damaging direction, but SpliceAI predicts no significant splice impact (max delta score = 0.02). A single moderately elevated BayesDel score does not constitute multiple lines of computational evidence. Furthermore, the predicted null effect of this nonsense variant is already captured by PVS1; applying PP3 for the same molecular consequence would constitute double-counting under ACMG/AMP guidance. Details ▾Hide ▴
Evidence considered
- SpliceAI: max delta score 0.02 — no significant splice impact predicted
- BayesDel: score 0.66 — single predictor in damaging direction
- REVEL: not available for this variant
- HCI Prior: not available for this gene
Sources
spliceai ↗bayesdel
BA1 BA1 requires an allele frequency >5% in any general population. NM_001904.4:c.802G>T is completely absent from gnomAD v2.1 (0 alleles), gnomAD v4.1 (0 alleles), and gnomAD-Canada v1.0 (0 alleles). This threshold is not met. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (0% allele frequency)
- Absent from gnomAD v4.1 (0% allele frequency)
Sources
BS1 BS1 requires an allele frequency greater than expected for the disorder (>0.3% under generic non-VCEP cutoffs). The variant is absent from gnomAD v2.1 and v4.1 (0 alleles). This threshold is not met. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (0% allele frequency)
- Absent from gnomAD v4.1 (0% allele frequency)
Sources
BS2 BS2 requires observation in a healthy adult individual for a fully penetrant dominant disorder. NM_001904.4:c.802G>T is completely absent from gnomAD across all populations. No confirmed observation in a healthy adult exists to support BS2. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 and v4.1 — no healthy adult carriers identified
Sources
BP4 BP4 requires multiple lines of computational evidence suggesting no impact on the gene product. BayesDel score of 0.66 is in the damaging direction, not the benign direction. SpliceAI predicts no splice impact (max delta 0.02), but this is a nonsense variant that introduces a premature stop codon — the predicted molecular consequence is damaging, not benign. Computational evidence does not support BP4. Details ▾Hide ▴
Evidence considered
- BayesDel: score 0.66 — damaging direction
- not benign
- SpliceAI: max delta 0.02 — no splice impact
- but irrelevant for nonsense variant
Sources
bayesdelspliceai ↗
Not assessed · 11 · no assessment recorded
PS2 The exploratory evidence pipeline identified a potential confirmed de novo report for this variant (PMID:32222192, Li et al. 2020 — reported de novo heterozygous c.802G>T in a patient with intellectual disability, microcephaly, and speech delay, with both parents confirmed negative). However, full-text is not available for verification per mandatory citation policy. Without confirmed parentage documentation in the retrievable evidence record, PS2 cannot be applied. Details ▾Hide ▴
Evidence considered
- Exploratory sub-agent identified PMID:32222192 as a potential confirmed de novo report — full-text unavailable for verification
Still missing
- Full-text of PMID:32222192 needed to confirm de novo status with confirmed parentage for this exact variant
PS3 No well-established functional studies (in vitro or in vivo) of NM_001904.4:c.802G>T are available in the evidence record. OncoKB lists an Unknown Oncogenic Effect with no variant-specific functional data. COSMIC reports no somatic entries for this variant. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect — no variant-specific functional annotation
- COSMIC: no entries for this variant
Still missing
- No functional assay data (e.g.
- NMD confirmation
- protein expression
- reporter assays) available for this variant
Sources
PS4 The variant is absent from ClinVar, so affected individuals cannot be tallied from that source. No verified publications containing proband counts for this exact variant were accessible for review. While the variant is completely absent from gnomAD (supporting rarity), the number of independently ascertained affected probands required for PS4 cannot be confirmed from the available evidence. Details ▾Hide ▴
Evidence considered
- ClinVar: absent — no affected probands can be tallied
- Literature search: no verified publications with variant-specific proband counts
Still missing
- Tally of independently ascertained probands from clinical databases and/or publications needed to evaluate PS4 strength
PM6 The exploratory evidence pipeline identified a possible assumed de novo record for this variant in DECIPHER, but parentage confirmation status could not be verified. No publications with de novo status (without confirmed parentage) for this exact variant are accessible for full-text review. Without verified evidence of de novo occurrence without parental confirmation, PM6 cannot be applied. Details ▾Hide ▴
Evidence considered
- Exploratory sub-agent identified a potential DECIPHER de novo entry — unverified
Still missing
- Verified assumed de novo observation (one parent tested
- or parentage not confirmed) would be needed for PM6
PP1 No cosegregation data is available. CTNNB1-related neurodevelopmental disorders are typically de novo with rare familial transmission. No published families with multiple affected members carrying this variant were identified in the available evidence. Details ▾Hide ▴
Evidence considered
- No cosegregation studies identified for this variant
Still missing
- Cosegregation data in affected families would be required to evaluate PP1
PP4 No detailed clinical phenotype information for individuals carrying NM_001904.4:c.802G>T was available for review. Patient phenotype specificity and fit to the CTNNB1-related neurodevelopmental disorder spectrum cannot be evaluated from the current evidence record. Details ▾Hide ▴
Still missing
- Clinical phenotype data for affected individuals carrying this variant is needed to evaluate PP4
PP5 No ClinVar entry exists for NM_001904.4:c.802G>T. PP5 requires a pathogenic classification from a reputable source (e.g., ClinVar); without such an entry, this criterion cannot be applied. Details ▾Hide ▴
Evidence considered
- ClinVar: absent — no reputable source classification available
Still missing
- A ClinVar entry with a pathogenic classification from a reputable source would enable PP5
BS3 No well-established in vitro or in vivo functional studies demonstrating no damaging effect on protein function or splicing are available for NM_001904.4:c.802G>T. Details ▾Hide ▴
Evidence considered
- No functional studies demonstrating a benign effect were identified
Still missing
- Well-established functional assays demonstrating no damaging effect would be needed for BS3
BP5 No ClinVar entry exists for NM_001904.4:c.802G>T, and no verified publication reports a benign classification for this variant from a reputable source. BP5 cannot be assessed without such evidence. Details ▾Hide ▴
Still missing
- A ClinVar entry or publication with a benign classification from a reputable source would be needed for BP5
BP6 No ClinVar entry exists for NM_001904.4:c.802G>T with a benign classification from a reputable source. BP6 cannot be assessed without such evidence. Details ▾Hide ▴
Still missing
- A ClinVar entry with a benign classification from a reputable source would be needed for BP6
PS5 No ClinVar entry exists for this variant, and no verified publications report a different pathogenic variant at the same amino acid position (codon 268) that could serve as a PS5 comparator. Without a validated comparator, PS5 cannot be applied. Details ▾Hide ▴
Evidence considered
- ClinVar: absent — no comparator variant at codon 268
Still missing
- No pathogenic variant at the same amino acid position (Gly268) with a different nucleotide change has been identified
Not applicable · 10· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 is designed for missense variants where a different nucleotide change results in the same amino acid substitution as an established pathogenic variant. For this nonsense variant (c.802G>T, p.G268*), no different nucleotide change at codon 268 creating a premature stop codon has been identified as a known pathogenic comparator in ClinVar or the available evidence. Details ▾Hide ▴
No further detail was recorded.
PM3 N/APM3 applies to recessive disorders where the variant is observed in trans with a pathogenic variant. CTNNB1-related neurodevelopmental disorder is autosomal dominant (MIM 615075). Details ▾Hide ▴
No further detail was recorded.
PM4 N/APM4 applies to in-frame deletions/insertions or stop-loss variants. NM_001904.4:c.802G>T is a nonsense (stop-gain) single-nucleotide substitution. Details ▾Hide ▴
No further detail was recorded.
PM5 N/AThe PM5 candidate search returned no same-residue comparator variants. PM5 is designed for missense variants at the same amino acid residue as a known pathogenic missense change. No applicable comparator exists for this nonsense variant at codon 268. Details ▾Hide ▴
Evidence considered
- PM5 candidate search: 0 same-residue candidates found
PP2 N/APP2 applies specifically to missense variants in genes with a low rate of benign missense variation and where missense is a common disease mechanism. NM_001904.4:c.802G>T is a nonsense variant, not a missense variant. HCI Prior data is not available for this gene. Details ▾Hide ▴
No further detail was recorded.
BS4 N/ABS4 evaluates lack of segregation in affected family members. CTNNB1-related neurodevelopmental disorders are typically de novo; no multigenerational family structures with affected members exist to evaluate segregation for this variant. BS4 is not applicable in this clinical context. Details ▾Hide ▴
No further detail was recorded.
BP1 N/ABP1 applies specifically to missense variants in genes where primarily truncating variants cause disease. NM_001904.4:c.802G>T (p.Gly268Ter) is itself a truncating (nonsense) variant, not a missense change. BP1 is not applicable. Details ▾Hide ▴
No further detail was recorded.
BP2 N/ABP2 applies when a variant is observed in trans with a known pathogenic variant for a recessive disorder. CTNNB1-related neurodevelopmental disorder is autosomal dominant (MIM 615075); no biallelic occurrences of CTNNB1 variants have been reported. BP2 is not applicable in this clinical context. Details ▾Hide ▴
No further detail was recorded.
BP3 N/ABP3 applies to in-frame deletions/insertions in repetitive regions; NM_001904.4:c.802G>T is a single-nucleotide substitution. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ABP7 applies specifically to synonymous (silent) variants for which splicing prediction algorithms predict no impact and the nucleotide is not highly conserved. NM_001904.4:c.802G>T is a nonsense variant that creates a premature termination codon (p.Gly268Ter). BP7 is not applicable. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- CTNNB1
- Transcript
- NM_001904.4
- Coding (HGVS c.)
- NM_001904.4:c.802G>T
- Protein (HGVS p.)
- NP_001895.1:p.(Gly268Ter)
- GRCh38
- chr3:41225727 G>T
- GRCh37
- chr3:41267218 G>T
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
—
Transcript span
—
Strand
—
Variants mapped
—
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
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
0 / 0 alleles
AF 0 · 0 homozygotes · FAF 0
By genetic ancestry
gnomAD-Canada
AF 0 · 0 / 0 alleles · 0 hom
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- 0.660
How the predictions were used
PP3 Multiple lines of computational evidence supporting a deleterious effect are not available. REVEL score is unavailable for this variant. BayesDel score of 0.66 provides a single in silico predictor in the damaging direction, but SpliceAI predicts no significant splice impact (max delta score = 0.02). A single moderately elevated BayesDel score does not constitute multiple lines of computational evidence. Furthermore, the predicted null effect of this nonsense variant is already captured by PVS1; applying PP3 for the same molecular consequence would constitute double-counting under ACMG/AMP guidance. Details ▾Hide ▴
Evidence considered
- SpliceAI: max delta score 0.02 — no significant splice impact predicted
- BayesDel: score 0.66 — single predictor in damaging direction
- REVEL: not available for this variant
- HCI Prior: not available for this gene
Sources
spliceai ↗bayesdel
BP4 BP4 requires multiple lines of computational evidence suggesting no impact on the gene product. BayesDel score of 0.66 is in the damaging direction, not the benign direction. SpliceAI predicts no splice impact (max delta 0.02), but this is a nonsense variant that introduces a premature stop codon — the predicted molecular consequence is damaging, not benign. Computational evidence does not support BP4. Details ▾Hide ▴
Evidence considered
- BayesDel: score 0.66 — damaging direction
- not benign
- SpliceAI: max delta 0.02 — no splice impact
- but irrelevant for nonsense variant
Sources
bayesdelspliceai ↗
BP7 N/ABP7 applies specifically to synonymous (silent) variants for which splicing prediction algorithms predict no impact and the nucleotide is not highly conserved. NM_001904.4:c.802G>T is a nonsense variant that creates a premature termination codon (p.Gly268Ter). BP7 is not applicable. Details ▾Hide ▴
No further detail was recorded.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). BayesDel score = 0.66.
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.020
Open source ↗
ClinVar
Captured ClinVar source record
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
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/?term=NM_001904.4%3Ac.802G%3ET
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/3-41267218-G-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr3-41225727-G-T?dataset=gnomad_r4
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001904.4%3Ac.802G…
- OncoKB ↗www.oncokb.org/gene/CTNNB1/G268*
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=CTNNB1+c.802G%3ET
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
ClinVar
This variant is absent from ClinVar.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). BayesDel score = 0.66.
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 not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.