CTNNB1 NM_001904.4:c.452G>A, p.(Arg151His) is present in gnomAD v4.1 at a total allele frequency of 0.000117726 (190/1613916) with a highest observed population frequency of 0.000154237 in European non-Finnish individuals, both below the non-VCEP PM2 rarity threshold of 0.001 (0.1%), supporting rarity but not absence from population databases.1 SpliceAI predicts a maximum delta score of 0.02, which is below the splice impact threshold of 0.2 and argues against a splice-disrupting effect.2 ClinVar contains conflicting single-submitter classifications of likely benign and uncertain significance, so this assertion set does not provide decisive classification evidence.3 In the absence of gene-specific criteria, robust case-level enrichment, segregation, de novo, or functional evidence, CTNNB1 p.(Arg151His) is classified as a variant of uncertain significance.
Final classification
Uncertain significance
PM2
CTNNB1
c.452G>A
p.Arg151His
This variant
CTNNB1 NM_001904.4:c.452G>A, p.(Arg151His) is present in gnomAD v4.1 at a total allele frequency of 0.000117726 (190/1613916) with a highest observed population frequency of 0.000154237 in European non-Finnish individuals, both below the non-VCEP PM2 rarity threshold of 0.001 (0.1%), supporting rarity but not absence from population databases.
generic_acmg
Classification rationale
PM2
Uncertain significance
CTNNB1 c.452G>A
PM2
→
Uncertain significance
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.
Gene diagram
· NM_001904.4 · variants mapped to exon structure
CTNNB1
NM_001904.4
Fetching transcript structure from UCSC…
Applied criteria · 1 applied · 23 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
review
Pathogenic
The variant is rare in population databases: gnomAD v4.1 total AF is 0.000117726 (190/1613916) and highest observed population AF is 0.000154237 in European non-Finnish individuals, both below the non-VCEP PM2 threshold of 0.001 (0.1%). gnomAD v2.1 also shows very low frequency (total AF 0.0000318573; highest population AF 0.000070466).
gnomAD v4.1 total AF 0.000117726; NFE AF 0.000154237gnomAD v2.1 total AF 0.0000318573; NFE AF 0.000070466
Assessed · not applied
· 6 not met · 17 not assessed
Pathogenic
PS1
No same-amino-acid pathogenic variant at this residue was documented in the reviewed workspace materials.
PS2
No de novo occurrence data with confirmed maternity and paternity were provided.
PS3
No validated functional assay results for CTNNB1 p.(Arg151His) were provided.
PS4
No case-control enrichment or multiple affected probands were established, and the PS4 literature screen did not identify supportive case evidence.
PM1
Cancer Hotspots did not identify residue Arg151 as a statistically significant hotspot, so PM1 is not supported by the assembled hotspot evidence.
PM3
No data on occurrence in trans with a pathogenic variant were provided.
PM5
No different pathogenic missense change at codon 151 was documented in the reviewed materials.
PM6
No assumed de novo occurrence without full parental confirmation was provided.
PP1
No segregation data were provided.
PP2
The reviewed workspace did not provide gene-level evidence sufficient to determine whether CTNNB1 has a low rate of benign missense variation and whether missense is a primary established disease mechanism for the relevant germline disorder.
PP3
SpliceAI shows a maximum delta score of 0.02, which is below the commonly used splice concern threshold of 0.2 and does not support splice disruption, and the available REVEL score of 0.466 is not sufficient on its own to establish deleterious computational evidence under a generic ACMG framework.
PP4
No phenotype or family history information specific enough to assess PP4 was provided.
PP5
PP5 was not applied.
Benign
BA1
The highest observed gnomAD v4.1 population AF is 0.000154237 (0.01542%), which is below the non-VCEP BA1 threshold of 0.01 (1%).
BS1
The highest observed gnomAD v4.1 population AF is 0.000154237 (0.01542%), which is below the non-VCEP BS1 threshold of 0.003 (0.3%).
BS2
No criterion-specific evidence for observation in healthy adults inconsistent with the expected penetrance or age of onset was provided.
BS3
No well-established functional studies demonstrating a benign effect were provided.
BS4
No segregation data demonstrating lack of cosegregation were provided.
BP1
The reviewed workspace did not provide gene-level disease-mechanism evidence sufficient to support BP1 for CTNNB1 missense variation.
BP2
No phase information showing the variant in trans with a pathogenic variant or in cis with another variant was provided.
BP4
SpliceAI predicts no meaningful splice impact with a max delta score of 0.02, which is below 0.2, but the available generic ACMG evidence set does not provide sufficient calibrated benign missense prediction evidence to apply BP4 because the REVEL score of 0.466 is intermediate and no gene-specific computational framework is available.
BP5
No alternate molecular diagnosis or established alternate cause for the phenotype was provided.
BP6
BP6 was not applied.
N/A · 4
PVS1 · PM4 · BP3 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 0.000117726; MAF= 0.01177%, 190/1613916 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000154237; MAF= 0.01542%, 182/1180000 alleles, homozygotes = 0); grpmax FAF= 0.00013971.
v2.1
This variant is present in gnomAD v2.1 (AF= 3.18573e-05; MAF= 0.00319%, 8/251120 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 7.0466e-05; MAF= 0.00705%, 8/113530 alleles, homozygotes = 0); grpmax FAF= 3.424e-05.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.012%
· 190 / 1,613,916
0 hom · FAF 0.014%
0 hom · FAF 0.014%
European (non-Finnish) 182 / 1,180,000 |
0.015% |
Remaining individuals 5 / 62,488 |
0.008% |
African/African American 2 / 74,912 |
0.0027% |
South Asian 1 / 91,084 |
0.0011% |
+ 6 not observed (Admixed American, European (Finnish), Middle Eastern, Ashkenazi Jewish, East Asian, Amish)
gnomAD v2.1
0.0032%
· 8 / 251,120
0 hom · FAF 0.0034%
0 hom · FAF 0.0034%
European (non-Finnish) 8 / 113,530 |
0.007% |
+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)
ClinVar
This variant has been reported in ClinVar as Likely benign (1 clinical laboratory) and as Uncertain significance (1 clinical laboratory).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).
Functional
OncoKB has not reviewed this specific variant; no variant-level oncogenicity or biological effect is available. Gene-level context: CTNNB1 (β-catenin), a transcriptional activator, is recurrently mutated in various cancers including endometrial and hepatocellular cancers.
COSMIC
Cancer hotspots
Somatic evidence
COSMIC
This variant has previously been reported in somatic cancers (COSMIC; COSV62702481, n = 2 times).
Hotspots
This variant does not lie in a statistically significant cancer hotspot.
Sources & reference links