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.1 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 BP4.2 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.3 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.4 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).5
CTNNB1
Final classification
VUS
PM2
CTNNB1
c.643G>A
p.Ala215Thr
This variant
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.
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.
Classification rationale
PM2
VUS
CTNNB1 c.643G>A
PM2
→
VUS
Gene diagram
· NM_001904.4 · variants mapped to exon structure
CTNNB1
NM_001904.4
Fetching transcript structure from UCSC…
Applied criteria · 1 applied · 22 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 1
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
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%.
gnomAD v2.1: 4/282282 allelesAF=1.42e-05 (0.0014%)
Assessed · not applied
· 22 not met · 0 not assessed
Pathogenic
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.
PS2
No de novo observation was identified for this variant in any available source.
PS3
No well-established functional studies demonstrating a damaging effect were identified for this variant.
PS4
No case-control or cohort data demonstrating statistically significant enrichment of this variant in affected individuals compared to controls.
PM1
The variant does not lie in a statistically significant mutational hotspot as assessed by the hotspot analysis.
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.
PM6
No de novo observation was identified for this variant.
PP1
No segregation data in affected family members was identified for this variant.
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.
PP3
Multiple in silico predictors do not support a deleterious effect.
PP4
No patient phenotype or family history data were available for independent evaluation.
PP5
No reputable source has classified this variant as pathogenic.
Benign
BA1
The variant is not present at an allele frequency >1% in any gnomAD population.
BS1
The variant allele frequency does not exceed the 0.3% threshold for BS1 in any population.
BS2
No specific evidence of this variant observed in a healthy adult individual in the context of a fully penetrant disorder was identified.
BS3
No well-established functional studies demonstrating no damaging effect were identified for this variant.
BS4
No segregation data in affected families is available to assess lack of segregation with disease.
BP1
CTNNB1-associated neurodevelopmental disorder is caused by both truncating and missense variants.
BP2
No evidence of this variant observed in trans with a pathogenic variant for a fully penetrant dominant disorder was identified.
BP4
Multiple lines of computational evidence do not provide compelling support for a benign effect.
BP5
No evidence of this variant found in a case with an alternate molecular basis for disease was identified.
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.
N/A · 3
PVS1 · BP3 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
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.
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.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.0038%
· 62 / 1,613,818
0 hom · FAF 0.0037%
0 hom · FAF 0.0037%
Remaining individuals 3 / 62,472 |
0.0048% |
European (non-Finnish) 55 / 1,179,980 |
0.0047% |
African/African American 2 / 74,904 |
0.0027% |
East Asian 1 / 44,886 |
0.0022% |
South Asian 1 / 91,068 |
0.0011% |
+ 5 not observed (Admixed American, European (Finnish), Amish, Middle Eastern, Ashkenazi Jewish)
gnomAD v2.1
0.0014%
· 4 / 282,282
0 hom · FAF 0.00029%
0 hom · FAF 0.00029%
East Asian 1 / 19,920 |
0.005% |
African/African American 1 / 24,950 |
0.004% |
European (non-Finnish) 2 / 128,882 |
0.0016% |
+ 5 not observed (Admixed American, Ashkenazi Jewish, European (Finnish), Remaining individuals, South Asian)
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
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
Unknown Oncogenic Effect
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.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV62719230, n = 1 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links