Starting

Initialising…

CTNNB1

Final classification

VUS

CTNNB1 c.1648C>T · p.Arg550Cys

CTNNB1

The CTNNB1 c.1648C>T (p.Arg550Cys; p.R550C) variant has been reported in ClinVar as a variant of uncertain significance by a single submitter.

Gene

CTNNB1

Transcript

NM_001904.4

HGVS · transcript:coding

NM_001904.4:c.1648C>T

Consequence

N/A

GRCh38

chr3:41234262 C>T

GRCh37

chr3:41275753 C>T

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.1648C>T

The CTNNB1 c.1648C>T (p.Arg550Cys; p.R550C) variant has been reported in ClinVar as a variant of uncertain significance by a single submitter.¹ This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity in the general population and meeting PM2 under the generic ACMG framework.² Available computational evidence is mixed: SpliceAI predicts no significant splice effect with a maximum delta score of 0.05, while REVEL is 0.507 and BayesDel is 0.164625, so the in silico data support neither PP3 nor BP4.³

PM2 → VUS

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗

3 spliceai ↗revelbayesdel

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

Absent from gnomAD v4.1.

v2.1

Absent from gnomAD v2.1.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory). (ClinVarID = 1388743)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.05). REVEL score = 0.507. BayesDel score = 0.164625.

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 not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

7Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 1 PMID not cited in assessment

28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR