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.
CTNNB1
Final classification
Uncertain significance
CTNNB1 c.452G>A · p.Arg151His
CTNNB1
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
Gene diagram
· NM_001904.4 · variants mapped to exon structure
CTNNB1
NM_001904.4
Fetching transcript structure from UCSC…
Applied criteria · 1 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
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