PM2 is met at moderate strength: this variant is absent from gnomAD v2.1 and is present at extremely low frequency in gnomAD v4.1 (1/1,614,112 alleles, AF=6.2e-07) and gnomAD Canada (2/18,420 alleles, AF=0.01%), all well below the 0.1% population frequency threshold.1 BP4 is met at supporting benign strength: multiple in silico predictors (REVEL 0.176, BayesDel -0.206, SpliceAI max delta 0.19) do not predict a damaging effect on protein function or splicing.2 All pathogenic criteria other than PM2 are not met: PS3 (no functional data), PP3 (in silico predictors favor benign, not pathogenic), PM1 (not in a hotspot or critical functional residue), PM5 (no pathogenic comparators at same residue), PS1/PS5 (no alternative nucleotide changes at same codon), PP5 (ClinVar VUS, not 3-star pathogenic).3 All benign criteria other than BP4 are not met: BA1/BS1 (population frequency too low), BP1 (missense is a known disease mechanism in CTNNB1), BP6 (ClinVar is VUS, not benign).4 With one moderate pathogenic criterion (PM2) and one supporting benign criterion (BP4), the overall classification is Uncertain Significance (VUS) per ACMG/AMP 2015 combination rules. The moderate evidence for rarity is partially offset by computational evidence suggesting no functional impact.5
CTNNB1
Final classification
VUS
CTNNB1 c.362A>C · p.Asn121Thr
CTNNB1
PM2 is met at moderate strength: this variant is absent from gnomAD v2.1 and is present at extremely low frequency in gnomAD v4.1 (1/1,614,112 alleles, AF=6.2e-07) and gnomAD Canada (2/18,420 alleles, AF=0.01%), all well below the 0.1% population frequency threshold.
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 moderate, BP4 supporting benign; combination = 1 moderate + 1 supporting benign, which maps to VUS.
Classification rationale
PM2
BP4
VUS
CTNNB1 c.362A>C
PM2 + BP4
→
VUS
2
revelbayesdelspliceai ↗
5
generic_acmg_combination_rules
Gene diagram
· NM_001904.4 · variants mapped to exon structure
CTNNB1
NM_001904.4
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 21 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
moderate
Pathogenic
This variant is present at extremely low frequency in population databases, well below the 0.1% threshold: absent from gnomAD v2.1 and present in only 1/1,614,112 alleles in gnomAD v4.1 (AF=6.2e-07, 0.000062%). gnomAD Canada reports 2/18,420 alleles (AF=0.01%, highest subpopulation NFE AF=0.017%).
gnomAD v2.1: absentgnomAD v4.1: 1/1614
✓
BP4
supporting
Benign
Multiple lines of computational evidence suggest this variant does not impact protein function: REVEL score 0.176 (below disease-causing threshold of 0.5), BayesDel score -0.206 (negative, favors benign), and SpliceAI max delta 0.19 (no predicted splicing impact).
REVEL: 0.176 (benign range)BayesDel: -0.206 (benign range)SpliceAI: max delta 0.19 (no predicted splicing alteration)
Assessed · not applied
Pathogenic
PS1
No evidence that a different nucleotide substitution at codon 121 producing the same amino acid change (p.Asn121Thr) has been reported as pathogenic in ClinVar or the literature.
PS2
No de novo data available for this variant; both maternity and paternity confirmation would be required.
PS3
No variant-specific functional data identified.
PS4
No case-control or prevalence data comparing affected individuals to controls available for this variant.
PM1
Residue 121 is not in a statistically significant mutational hotspot (cancerhotspots.org negative).
PM5
No pathogenic missense variants at the same amino acid residue (codon 121) were identified in ClinVar.
PM6
No de novo observation reported for this variant.
PP1
No co-segregation data available for this variant.
PP2
Although CTNNB1 missense variants are a known mechanism of neurodevelopmental disease (CTNNB1 syndrome), no specific missense constraint metric (e.g., Z-score) was available to establish a low rate of benign missense variation in this gene.
PP3
Multiple in silico predictors do not support a deleterious effect: REVEL score 0.176 (below 0.5 threshold, favors benign), BayesDel score -0.206 (negative, favors benign), SpliceAI max delta 0.19 (below 0.2 threshold, no splicing impact predicted).
PP4
No patient-specific phenotype or clinical data available for assessment.
PP5
ClinVar classification is Uncertain significance from a single clinical laboratory (Labcorp/Invitae), with review status 'criteria provided, single submitter' (1 star).
Benign
BA1
The highest observed allele frequency is 0.017% (gnomAD Canada, NFE population), which is well below the BA1 threshold of >1%.
BS1
The highest observed allele frequency is 0.017% (gnomAD Canada, NFE population), which is below the BS1 threshold of >0.3%.
BS2
No data available regarding observation of this variant in healthy adult individuals to assess for full-penetrance expectation mismatch.
BS3
No functional studies demonstrating a neutral or benign effect for this variant have been identified.
BS4
No segregation data available to assess lack of co-segregation with disease.
BP1
CTNNB1 missense variants are a known disease mechanism for CTNNB1-associated neurodevelopmental disorder (PMID:33350591).
BP2
No data available on observation of this variant in trans with a pathogenic variant.
BP5
No data available indicating this variant is found in a case with an alternate molecular basis for disease.
BP6
ClinVar classification is Uncertain significance (1 star, single submitter), not benign.
N/A · 5
PVS1 · PM3 · PM4 · BP3 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 6.19536e-07; MAF= 0.00006%, 1/1614112 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.4746e-07; MAF= 0.00008%, 1/1179996 alleles, homozygotes = 0).
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
This variant is present in gnomAD-Canada v1.0 (AF= 0.00010857763300760044, 2/18420 alleles, homozygotes = 0).
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
6.2e-05%
· 1 / 1,614,112
0 hom
0 hom
European (non-Finnish) 1 / 1,179,996 |
8.5e-05% |
+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
0.011%
· 2 / 18,420
0 hom · FAF 0.003%
0 hom · FAF 0.003%
European (non-Finnish) 2 / 11,740 |
0.017% |
+ 8 not observed (African/African American, Latino/Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Middle Eastern, Remaining individuals, South Asian)
ClinVar
This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory). (ClinVarID = 1398665)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.19). REVEL score = 0.176. BayesDel score = -0.205682.
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 not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links