About CTNNB1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
CTNNB1 c.643G>A, p.(Ala215Thr)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
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: 1
Benign evidence criteria: 0
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
This variant is present at extremely low frequency in population databases, meeting the PM2 threshold (<0.1%). In gnomAD v2.1, it is observed in 4 of 282,282 alleles (AF=0.00142%, no homozygotes) with a grpmax filtering allele frequency of 2.93e-06. In gnomAD v4.1, it is observed in 62 of 1,613,818 alleles (AF=0.00384%, no homozygotes) with a grpmax FAF of 3.67e-05. It is absent from gnomAD-Canada. All population sub-cohort frequencies are well below 0.1%.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting; combination = 1 supporting, which maps to VUS.
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
62 / 1,613,818 alleles
gnomAD v4.1: 62 / 1,613,818 alleles. Recorded AF 3.84182e-05. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.41702e-05; MAF= 0.00142%, 4/282282 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 5.02008e-05; MAF= 0.00502%, 1/19920 alleles, homozygotes = 0); grpmax FAF= 2.93e-06.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
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
2 reported laboratory submissions
1 Likely benign · 1 Uncertain significance.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. CTNNB1 (β-catenin), a transcriptional activator, is recurrently mutated in various cancers including endometrial and hepatocellular cancers.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
1 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV62719230, n = 1 times).
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.
27 criteria with recorded statuses: 1 met · 23 not met · 0 not assessed · 3 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
This variant is present at extremely low frequency in population databases (gnomAD v2.1: 4/282,282 alleles, AF=0.0014%; gnomAD v4.1: 62/1,613,818 alleles, AF=0.0038%; absent from gnomAD-Canada), meeting PM2 at supporting strength.
In silico predictors do not support a deleterious effect: REVEL score is 0.278, BayesDel is 0.13681, and SpliceAI predicts no splicing impact (max delta 0.02). However, these scores are insufficient to independently meet BP4.
This variant has been reported in ClinVar as Likely benign by one clinical laboratory (GeneDx) and as Uncertain significance by another (Labcorp/Invitae). No pathogenic classification has been asserted by any submitter.
No functional studies, segregation data, de novo observations, or variant-specific publications were identified for this variant. OncoKB reports Unknown Oncogenic Effect with no curated functional evidence.
With only one supporting-level pathogenic criterion (PM2) met and no benign criteria met, the evidence is insufficient to classify this variant as either pathogenic or benign. This variant is classified as a Variant of Uncertain Significance (VUS) under generic ACMG/AMP 2015 rules (PMID:25741868).
No criteria match.
Met · 1
PM2 SupportingThis variant is present at extremely low frequency in population databases, meeting the PM2 threshold (<0.1%). In gnomAD v2.1, it is observed in 4 of 282,282 alleles (AF=0.00142%, no homozygotes) with a grpmax filtering allele frequency of 2.93e-06. In gnomAD v4.1, it is observed in 62 of 1,613,818 alleles (AF=0.00384%, no homozygotes) with a grpmax FAF of 3.67e-05. It is absent from gnomAD-Canada. All population sub-cohort frequencies are well below 0.1%. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: 4/282
- 282 alleles
- AF=1.42e-05 (0.0014%)
- 0 homozygotes
- grpmax FAF=2.93e-06
- gnomAD v4.1: 62/1
- 613
- 818 alleles
- AF=3.84e-05 (0.0038%)
- grpmax FAF=3.67e-05
- gnomAD-Canada v1.0: absent (0 alleles)
Sources
Not met · 23 · evaluated, threshold not reached
PS1 No evidence of a different nucleotide change at this codon resulting in the same amino acid substitution (p.Ala215Thr) that has been established as pathogenic. The only ClinVar entries for this residue are for the identical variant c.643G>A, classified as Likely benign and Uncertain significance. Details ▾Hide ▴
Evidence considered
- ClinVar variation ID 1200393 contains only submissions for c.643G>A with classifications of Likely benign and Uncertain significance
- no alternative nucleotide change at codon 215 with a pathogenic classification was identified.
Sources
PS2 No de novo observation was identified for this variant in any available source. No parental genotype data was available. Details ▾Hide ▴
Still missing
- No de novo testing data or parental genotype information available.
PS3 No well-established functional studies demonstrating a damaging effect were identified for this variant. OncoKB reports Unknown Oncogenic Effect with no variant-specific curated functional evidence. No publications with functional data for NM_001904.4:c.643G>A were retrieved. Details ▾Hide ▴
Evidence considered
- OncoKB classification for CTNNB1 A215T is 'Unknown Oncogenic Effect' with no reviewed functional evidence for this specific variant.
Still missing
- No functional assay data available for p.Ala215Thr.
Sources
PS4 No case-control or cohort data demonstrating statistically significant enrichment of this variant in affected individuals compared to controls. The variant is observed at extremely low frequency in gnomAD (4/282,282 in v2.1; 62/1,613,818 in v4.1) and has been reported in ClinVar by only two clinical laboratories without associated patient phenotype data. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: 4/282
- 282 alleles (AF=1.42e-05)
- gnomAD v4.1: 62/1
- 613
- 818 alleles (AF=3.84e-05)
- ClinVar: 2 submissions (Likely benign
- Uncertain significance) without aggregated case-level phenotype data.
Still missing
- No case-control study or phenotype-linked cohort data available.
Sources
PM1 The variant does not lie in a statistically significant mutational hotspot as assessed by the hotspot analysis. While p.Ala215 is located within the armadillo repeat domain of β-catenin, no domain-specific constraint metrics or hotspot enrichment data were provided to support PM1 application under generic ACMG/AMP rules. Details ▾Hide ▴
Evidence considered
- Hotspot analysis: residue not statistically significant
- exact variant not listed in hotspot database.
Still missing
- No domain-specific constraint or enrichment data available for CTNNB1 armadillo repeat domains.
PM5 No pathogenic missense variant at the same amino acid residue (p.Ala215) with a different amino acid change was identified in ClinVar or other sources. Automated PM5 candidate harvesting was unable to confirm classic same-residue semantics. Details ▾Hide ▴
Evidence considered
- PM5 candidate search returned 0 same-residue candidates
- no alternative missense change at codon 215 classified as pathogenic.
Sources
pm5_candidates
PM6 No de novo observation was identified for this variant. PM6 requires a confirmed de novo event; no such evidence is available. Details ▾Hide ▴
Still missing
- No de novo testing data available.
PP1 No segregation data in affected family members was identified for this variant. Details ▾Hide ▴
Still missing
- No family segregation data available.
PP2 While CTNNB1 missense variants are an established disease mechanism in CTNNB1-associated neurodevelopmental disorder, no gene-level missense constraint metrics (e.g., missense Z-score, observed/expected ratio) were provided to support PP2 application under generic ACMG/AMP rules. Details ▾Hide ▴
Evidence considered
- CTNNB1 is associated with autosomal dominant neurodevelopmental disorder caused by both truncating and missense variants
- but no quantitative missense constraint data were available.
Still missing
- No gene-level missense constraint metrics (Z-score
- OE ratio) available in the evidence packet.
PP3 Multiple in silico predictors do not support a deleterious effect. REVEL score is 0.278 (below typical pathogenic threshold of >0.5), BayesDel score is 0.13681 (benign-leaning), and SpliceAI predicts no significant splice impact (max delta score = 0.02). Combined computational evidence does not support a damaging effect. Details ▾Hide ▴
Evidence considered
- REVEL score: 0.278
- BayesDel score: 0.13681
- SpliceAI max delta: 0.02 (no predicted splice impact)
Sources
PP4 No patient phenotype or family history data were available for independent evaluation. The variant has been reported in ClinVar with non-specific indications (one submission for 'Not Provided'), which does not support a highly specific phenotype. Details ▾Hide ▴
Evidence considered
- ClinVar submissions: GeneDx (Likely benign
- condition: 'Not Provided')
- Labcorp/Invitae (Uncertain significance
- no condition labels).
Still missing
- No detailed phenotype or family history data available.
Sources
PP5 No reputable source has classified this variant as pathogenic. ClinVar classifications for this variant are Likely benign (GeneDx) and Uncertain significance (Labcorp/Invitae), neither of which supports a pathogenic assertion. Details ▾Hide ▴
Evidence considered
- ClinVar variation 1200393: Likely benign (1 submitter) and Uncertain significance (1 submitter)
- no pathogenic classification.
Sources
BA1 The variant is not present at an allele frequency >1% in any gnomAD population. The highest observed subpopulation frequency is 0.026% in EAS_KOR (gnomAD v2.1) and 0.0048% in the Remaining population (gnomAD v4.1), both far below the BA1 threshold of 1%. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 max subpopulation AF: 0.026% (EAS_KOR
- 1/3
- 794)
- gnomAD v4.1 max subpopulation AF: 0.0048% (Remaining
- 3/62
- 472)
Sources
BS1 The variant allele frequency does not exceed the 0.3% threshold for BS1 in any population. The highest subpopulation frequency is 0.026% (EAS_KOR in gnomAD v2.1), well below the BS1 cutoff. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 max subpopulation AF: 0.026% (EAS_KOR)
- gnomAD v4.1 max subpopulation AF: 0.0048% (Remaining)
- All populations below 0.3% BS1 threshold
Sources
BS2 No specific evidence of this variant observed in a healthy adult individual in the context of a fully penetrant disorder was identified. While the variant is present in gnomAD (presumed healthy population cohorts), the frequency is too low to independently support BS2, and no individual case-level healthy adult observation data are available. Details ▾Hide ▴
Still missing
- No individual-level healthy adult observation data available.
BS3 No well-established functional studies demonstrating no damaging effect were identified for this variant. No variant-specific functional data are available from OncoKB or the literature. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect
- no functional evidence for this variant.
Still missing
- No functional assay data for p.Ala215Thr.
Sources
BS4 No segregation data in affected families is available to assess lack of segregation with disease. Details ▾Hide ▴
Still missing
- No family segregation data available.
BP1 CTNNB1-associated neurodevelopmental disorder is caused by both truncating and missense variants. BP1 is applicable only when a gene primarily causes disease through truncating variants, which is not the case for CTNNB1 where missense variants are an established pathogenic mechanism. Details ▾Hide ▴
Evidence considered
- CTNNB1 syndrome literature (e.g.
- PMID:36083290
- PMID:33350591) reports pathogenic missense variants in addition to truncating variants.
BP2 No evidence of this variant observed in trans with a pathogenic variant for a fully penetrant dominant disorder was identified. No phase data are available. Details ▾Hide ▴
Still missing
- No phase or trans configuration data available.
BP4 Multiple lines of computational evidence do not provide compelling support for a benign effect. REVEL score of 0.278 is in an indeterminate range, BayesDel score of 0.13681 is benign-leaning, and SpliceAI max delta of 0.02 predicts no splicing impact. However, the in silico evidence is not sufficiently strong or concordant to meet BP4; the REVEL score does not clearly fall into a benign range. Details ▾Hide ▴
Evidence considered
- REVEL score: 0.278 (indeterminate
- below typical benign cutoff of <0.2)
- BayesDel score: 0.13681 (benign-leaning)
- SpliceAI max delta: 0.02 (no predicted splicing impact)
Sources
BP5 No evidence of this variant found in a case with an alternate molecular basis for disease was identified. Details ▾Hide ▴
Still missing
- No data on alternative molecular diagnoses in carriers.
BP6 While ClinVar contains a Likely benign classification (GeneDx, SCV001788747), this classification was based on evaluable evidence (criteria provided, single submitter) and does not meet the BP6 requirement of a reputable source report without accessible evidence. The underlying evidence is accessible and has been independently assessed. Details ▾Hide ▴
Evidence considered
- ClinVar SCV001788747 (GeneDx): Likely benign
- criteria provided
- single submitter. Classification is evaluable and accessible
- evidence does not require BP6 proxy.
Sources
PS5 No evidence of this variant found in trans with a pathogenic variant for a recessive disorder. CTNNB1-associated disease is autosomal dominant; this criterion is generally not applicable to dominant disorders in the absence of a specific recessive phenotype. Details ▾Hide ▴
No further detail was recorded.
Not applicable · 3· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant (p.Ala215Thr) that does not fall into the generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants. PVS1 is not applicable to missense substitutions under the ClinGen SVI PVS1 framework (PMC6185798). Details ▾Hide ▴
No further detail was recorded.
BP3 N/AThis criterion applies to in-frame insertions/deletions in repetitive regions; the variant is a missense substitution. Details ▾Hide ▴
No further detail was recorded.
BP7 N/AThis is a missense variant (c.643G>A, p.Ala215Thr), not a synonymous (silent) variant. BP7 is only applicable to synonymous variants without predicted splice impact. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- CTNNB1
- Transcript
- NM_001904.4
- Coding (HGVS c.)
- NM_001904.4:c.643G>A
- Protein (HGVS p.)
- NP_001895.1:p.(Ala215Thr)
- GRCh38
- chr3:41225481 G>A
- GRCh37
- chr3:41266972 G>A
- ClinVar
- 1200393
- COSMIC
- COSV62719230
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
62 / 1,613,818 alleles
AF 3.84e-05 · 0 homozygotes · FAF 3.67e-05
gnomAD v2.1
4 / 282,282 alleles
AF 1.42e-05 · 0 homozygotes · FAF 2.93e-06
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 3.8e-05 · 62 / 1,613,818 alleles · 0 hom · FAF 3.7e-05
| Remaining individuals3 / 62,472 | 4.8e-05 |
| European (non-Finnish)55 / 1,179,980 | 4.7e-05 |
| African/African American2 / 74,904 | 2.7e-05 |
| East Asian1 / 44,886 | 2.2e-05 |
| South Asian1 / 91,068 | 1.1e-05 |
0 alternate alleles recorded in 5 other groups: Admixed American, European (Finnish), Amish, Middle Eastern, Ashkenazi Jewish.
gnomAD v2.1
AF 1.4e-05 · 4 / 282,282 alleles · 0 hom · FAF 2.9e-06
| East Asian1 / 19,920 | 5e-05 |
| African/African American1 / 24,950 | 4e-05 |
| European (non-Finnish)2 / 128,882 | 1.6e-05 |
0 alternate alleles recorded in 5 other groups: Admixed American, Ashkenazi Jewish, European (Finnish), Remaining individuals, South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 3.84182e-05; MAF= 0.00384%, 62/1613818 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 4.80215e-05; MAF= 0.00480%, 3/62472 alleles, homozygotes = 0); grpmax FAF= 3.666e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.41702e-05; MAF= 0.00142%, 4/282282 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 5.02008e-05; MAF= 0.00502%, 1/19920 alleles, homozygotes = 0); grpmax FAF= 2.93e-06.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.278
- BayesDel
- 0.137
How the predictions were used
PP3 Multiple in silico predictors do not support a deleterious effect. REVEL score is 0.278 (below typical pathogenic threshold of >0.5), BayesDel score is 0.13681 (benign-leaning), and SpliceAI predicts no significant splice impact (max delta score = 0.02). Combined computational evidence does not support a damaging effect. Details ▾Hide ▴
Evidence considered
- REVEL score: 0.278
- BayesDel score: 0.13681
- SpliceAI max delta: 0.02 (no predicted splice impact)
Sources
BP4 Multiple lines of computational evidence do not provide compelling support for a benign effect. REVEL score of 0.278 is in an indeterminate range, BayesDel score of 0.13681 is benign-leaning, and SpliceAI max delta of 0.02 predicts no splicing impact. However, the in silico evidence is not sufficiently strong or concordant to meet BP4; the REVEL score does not clearly fall into a benign range. Details ▾Hide ▴
Evidence considered
- REVEL score: 0.278 (indeterminate
- below typical benign cutoff of <0.2)
- BayesDel score: 0.13681 (benign-leaning)
- SpliceAI max delta: 0.02 (no predicted splicing impact)
Sources
BP7 N/AThis is a missense variant (c.643G>A, p.Ala215Thr), not a synonymous (silent) variant. BP7 is only applicable to synonymous variants without predicted splice impact. Details ▾Hide ▴
No further detail was recorded.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.278. BayesDel score = 0.13681.
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
62 / 1,613,818 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.020
Open source ↗
ClinVar
1 Likely benign · 1 Uncertain significance
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/variation/1200393/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/3-41266972-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr3-41225481-G-A?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/3-41225481-G-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001904.4%3Ac.643G…
- OncoKB ↗www.oncokb.org/gene/CTNNB1/A215T
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=223280476
- 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
This variant is present in gnomAD v4.1 (AF= 3.84182e-05; MAF= 0.00384%, 62/1613818 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 4.80215e-05; MAF= 0.00480%, 3/62472 alleles, homozygotes = 0); grpmax FAF= 3.666e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.41702e-05; MAF= 0.00142%, 4/282282 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 5.02008e-05; MAF= 0.00502%, 1/19920 alleles, homozygotes = 0); grpmax FAF= 2.93e-06.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Likely benign (1 clinical laboratory) and as Uncertain significance (1 clinical laboratory). (ClinVarID = 1200393)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.278. BayesDel score = 0.13681.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. CTNNB1 (β-catenin), a transcriptional activator, is recurrently mutated in various cancers including endometrial and hepatocellular cancers.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV62719230, n = 1 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.