Starting

Initialising…

CTNNB1

Final classification

VUS

CTNNB1 c.269G>A · p.Arg90Gln

CTNNB1

Gene

CTNNB1

Transcript

NM_001904.4

HGVS · transcript:coding

NM_001904.4:c.269G>A

Consequence

N/A

GRCh38

chr3:41224981 G>A

GRCh37

chr3:41266472 G>A

Basis 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; combination = 1 moderate, which maps to VUS. ▾

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; combination = 1 moderate, which maps to VUS.

Classification rationale

PM2 VUS

CTNNB1 c.269G>A

NM_001904.4:c.269G>A (p.Arg90Gln) is at extremely low frequency in population databases: absent from gnomAD v2.1 and gnomAD-Canada with 1 allele out of 1,613,962 in gnomAD v4.1 (AF 0.000062%), meeting PM2 at moderate strength.¹ This variant has been reported in ClinVar as Uncertain significance by a single clinical laboratory (VariationID 1378784).² In silico predictors are equivocal (REVEL 0.455, BayesDel 0.221, SpliceAI delta 0.0) and do not meet thresholds for PP3 or BP4.³ This variant has been observed in somatic cancers (COSMIC COSV62707932, n = 2); no germline functional evidence is available.⁴ No de novo, segregation, case-control, or functional data are available for this variant. Multiple criteria remain unassessed.

PM2 → VUS

1 gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

2 clinvar ↗

3 revelbayesdelspliceai ↗

4 oncokb ↗

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

Benign evidence

—

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= 6.19593e-07; MAF= 0.00006%, 1/1613962 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47502e-07; MAF= 0.00008%, 1/1179938 alleles, homozygotes = 0).

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

6.2e-05% · 1 / 1,613,962
0 hom

European (non-Finnish)

1 / 1,179,938

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

Not observed in any ancestry group.

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory). (ClinVarID = 1378784)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.455. BayesDel score = 0.220613.

SpliceAI ↗

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.

OncoKB ↗

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; COSV62707932, n = 2 times).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots