NM_001904.3:c.47C>T (p.Pro16Leu) is a missense variant in CTNNB1 absent from gnomAD v2.1 and v4.1 population databases (PM2).1 Multiple in silico tools (REVEL 0.153, BayesDel -0.111, SpliceAI max delta 0.01) concordantly predict a neutral effect (BP4).2 No de novo observations, case-control data, functional studies, segregation data, or ClinVar classifications are available for this variant. The variant has been reported once in the somatic COSMIC database (COSV62719848) but has no established somatic or germline clinical significance. With one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4), the net evidence is equivocal. Applying generic ACMG/AMP 2015 combination rules (PMID:25741868), this variant is classified as a Variant of Uncertain Significance (VUS).3
CTNNB1
Final classification
VUS
CTNNB1 c.47C>T · p.Pro16Leu
CTNNB1
NM_001904.3:c.47C>T (p.Pro16Leu) is a missense variant in CTNNB1 absent from gnomAD v2.1 and v4.1 population databases (PM2).
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, BP4 supporting benign; combination = 1 supporting + 1 supporting benign, which maps to VUS.
Classification rationale
PM2
BP4
VUS
CTNNB1 c.47C>T
PM2 + BP4
→
VUS
Gene diagram
· NM_001904.3 · variants mapped to exon structure
CTNNB1
NM_001904.3
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 21 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
NM_001904.3:c.47C>T is absent from gnomAD v2.1 and v4.1 population databases, meeting the <0.1% threshold for PM2 in the non-VCEP generic ACMG/AMP framework.
Absent from gnomAD v2.1 (AF=0) and gnomAD v4.1 (AF=0).
✓
BP4
supporting
Benign
Multiple lines of computational evidence support a benign interpretation: REVEL score 0.153 (well below 0.5 threshold), BayesDel score -0.111 (below zero), and SpliceAI max delta score 0.01 (no predicted splicing impact). All three in silico predictors are concordant for a neutral effect.
REVEL 0.153BayesDel -0.111SpliceAI max delta 0.01 — all predict benign/neutral.
Assessed · not applied
Pathogenic
PS1
PS1 requires a different nucleotide change at the same codon with established pathogenicity.
PS2
PS2 requires a de novo observation with confirmed paternity and maternity.
PS3
PS3 requires well-established in vitro or in vivo functional studies demonstrating a damaging effect.
PS4
PS4 requires significantly increased prevalence of the variant in affected individuals versus controls.
PM1
p.Pro16 lies in the N-terminal domain (residues 1-138) but is N-terminal to the well-characterized GSK-3beta phosphorylation hotspot at codons 32-45.
PM5
PM5 requires a different pathogenic missense change at the same residue (Pro16).
PM6
PM6 applies to presumed de novo variants without confirmed paternity/maternity.
PP1
PP1 requires cosegregation of the variant with disease in multiple affected family members.
PP2
PP2 applies to missense variants in genes with a low rate of benign missense variation where missense is a common disease mechanism.
PP3
Multiple in silico tools support a benign interpretation: REVEL score 0.153 (well below 0.5 threshold), BayesDel score -0.111 (below zero, benign-leaning), and SpliceAI max delta score 0.01 (no predicted splicing impact).
PP4
PP4 requires a patient phenotype or family history highly specific for the gene.
PP5
PP5 requires a reputable source to have reported the variant as pathogenic.
Benign
BA1
BA1 requires an allele frequency >1% (non-VCEP threshold).
BS1
BS1 requires an allele frequency >0.3% (non-VCEP threshold), greater than expected for the disorder.
BS2
BS2 requires observation of the variant in a healthy adult individual, in a gene where full penetrance is expected at an early age.
BS3
BS3 requires well-established in vitro or in vivo functional studies demonstrating no damaging effect.
BS4
BS4 requires nonsegregation of the variant with disease in affected family members.
BP1
BP1 applies to a missense variant in a gene where primarily truncating variants cause disease.
BP2
BP2 requires observation in trans with a known pathogenic variant for a recessive disorder, or in cis with a pathogenic variant for a dominant disorder.
BP5
BP5 requires identification of an alternate molecular basis for disease in a case carrying the variant.
BP6
BP6 requires a reputable source to have reported the variant as benign.
N/A · 3
PVS1 · BP3 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.153. BayesDel score = -0.111224.
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; COSV62719848, n = 1 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links