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

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 · 21 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 moderate Pathogenic

This variant is absent from gnomAD v2.1 and gnomAD v4.1, so its population frequency is below the non-VCEP PM2 threshold of 0.1%, supporting rarity in the general population.

Absent from gnomAD v2.1Absent from gnomAD v4.1

gnomad_v2 ↗gnomad_v4 ↗

Assessed · not applied · 6 not met · 15 not assessed

Pathogenic

PS1 No established pathogenic variant causing the same amino acid change was identified in the available evidence, so PS1 was not assessed.

PS2 No confirmed de novo occurrence of this variant with a consistent phenotype and documented parental relationships was identified, so PS2 was not assessed.

PS3 No well-established functional study of this exact variant was identified showing a damaging effect, so PS3 was not assessed.

PS4 Available evidence does not show that this variant is significantly enriched in affected individuals compared with controls, so PS4 was not assessed.

PM1 Available evidence does not show that codon 550 lies in a well-established mutational hotspot or a critical domain without benign variation.

PM5 No pathogenic or likely pathogenic missense comparator at the same residue was identified in the available evidence, and automated candidate review did not find usable same-residue comparators, so PM5 is not met.

PM6 No assumed de novo occurrence of this variant without full parental confirmation was identified, so PM6 was not assessed.

PP1 No segregation data were identified for this variant, so PP1 was not assessed.

PP2 Available evidence does not provide a gene-specific missense-constraint framework for applying PP2 to this variant, so PP2 was not assessed.

PP3 Computational evidence is mixed and does not consistently support a damaging effect.

PP4 No phenotype information for an affected individual carrying this variant was provided, so PP4 was not assessed.

Benign

BA1 This variant was absent from gnomAD v2.1 and gnomAD v4.1, so its population frequency is far below the benign BA1 threshold of 1%.

BS1 This variant was absent from gnomAD v2.1 and gnomAD v4.1, so its population frequency does not exceed the benign BS1 threshold of 0.3%.

BS2 No evidence was identified showing this variant in healthy adult individuals in a context sufficient for BS2, so BS2 was not assessed.

BS3 No well-established functional study of this exact variant was identified showing normal function, so BS3 was not assessed.

BS4 No family data were identified showing lack of segregation with disease, so BS4 was not assessed.

BP1 Available evidence does not provide a supported gene-level framework for applying BP1 to this missense variant, so BP1 was not assessed.

BP2 No evidence was identified that this variant occurs in cis with a pathogenic variant or in trans with a pathogenic variant in a fully explained dominant case, so BP2 was not assessed.

BP3 No evidence was identified that this variant lies in a repetitive region without known function, so BP3 was not assessed.

BP4 Computational evidence does not consistently support a benign effect.

BP5 No case-specific phenotype data or alternative molecular diagnosis were provided, so BP5 was not assessed.

N/A · 6 PVS1 · PM3 · PM4 · PP5 · BP6 · 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.

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

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