NM_001903.5:c.1618C>T

CTNNA1 · NP_001894.2:p.(Arg540Cys) · NM_001903.5

GRCh37: chr5:138260270 C>T · GRCh38: chr5:138924581 C>T

Gene: CTNNA1 Transcript: NM_001903.5

Final call

VUS

PM2 supporting

Variant details

Gene

CTNNA1

Transcript

NM_001903.5

Protein

NP_001894.2:p.(Arg540Cys)

gnomAD AF

6.815390887450635e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

The CTNNA1 c.1618C>T (p.Arg540Cys) variant has been reported in ClinVar, where it is currently classified as uncertain significance by 4 clinical laboratories without expert panel review.

This variant is rare in population databases, with gnomAD v2.1 showing 1/251442 alleles (0.00040%) and gnomAD v4.1 showing 11/1613994 alleles (0.00068%), both below the 0.1% PM2 threshold and with no homozygotes observed.

No variant-specific well-established functional study was identified for p.Arg540Cys in the retrieved materials.

In silico evidence is not concordant enough to support either PP3 or BP4: SpliceAI predicts no splice impact (max delta score 0.00), while REVEL is 0.305 and BayesDel is 0.105968.

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	This is a missense variant, NM_001903.5:c.1618C>T (p.Arg540Cys), and it does not fall into the generic PVS1 null-variant categories of nonsense, frameshift, or canonical +/-1,2 splice variants, so PVS1 is not applicable.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework
PS1	Not assessed	No evidence was identified showing that this nucleotide change creates the same amino acid substitution as a previously established pathogenic variant.	clinvar
PS2	Not assessed	No confirmed de novo occurrence data were identified for this variant.	clinvar
PS3	Not assessed	No variant-specific well-established functional study was identified for p.Arg540Cys. Available CTNNA1 literature in the retrieved materials focused on loss-of-function disease context rather than direct functional testing of this missense change.	oncokb PMID:32051609
PS4	Not met	This variant is listed in ClinVar as uncertain significance by 4 clinical laboratories, but no case-control enrichment, prevalence data, or statistically increased occurrence in affected individuals were identified.	clinvar PMID:32051609
PM1	Not met	This variant was not identified in a statistically significant mutational hotspot, and no well-established critical functional domain enrichment evidence was identified for residue Arg540.	hotspots
PM2	Met	This variant is rare in population databases. In gnomAD v2.1 it is present at 1/251442 alleles (AF 0.00040%), and in gnomAD v4.1 at 11/1613994 alleles (AF 0.00068%), both well below the 0.1% PM2 threshold, with no homozygotes observed.	gnomad_v2 gnomad_v4 gnomad_canada
PM3	Not assessed	No evidence was identified showing this variant in trans with a pathogenic variant in a recessive disease context.	clinvar
PM4	N/A	PM4 applies to protein length changes such as in-frame insertions/deletions or stop-loss variants, which is not the variant type observed here.
PM5	N/A	A same-residue PM5 comparison was not applied because the available review materials could not safely confirm that classic same-residue PM5 logic should be used for this gene/framework, and no validated comparator variant set was established.	pm5_candidates
PM6	Not assessed	No assumed de novo occurrence data were identified for this variant.	clinvar
PP1	Not assessed	No segregation data were identified for this variant.	clinvar PMID:32051609
PP2	Not assessed	Available evidence does not establish CTNNA1 as a gene in which missense variation is a common disease mechanism with a low rate of benign missense variation, so PP2 was not applied.	pvs1_gene_context PMID:32051609
PP3	Not met	Available computational evidence does not provide consistent support for a damaging effect. SpliceAI predicts no meaningful splice impact (max delta score 0.00), REVEL is 0.305, and BayesDel is 0.105968; together these results do not reach a clear PP3 threshold.	spliceai revel bayesdel
PP4	Not assessed	No phenotype data specific enough to support a highly CTNNA1-specific clinical presentation were identified for this variant.	clinvar
PP5	Not met	No reputable source classification supporting pathogenicity beyond single-submitter uncertain-significance assertions was identified for this variant.	clinvar
BA1	Not met	Population frequency is far below the standalone benign threshold. The highest observed gnomAD v4.1 overall frequency is 0.00068%, which is well below 1%.	gnomad_v4
BS1	Not met	Population frequency does not exceed the benign strong threshold. The highest observed overall gnomAD frequency is 0.00068%, which is below the 0.3% BS1 threshold.	gnomad_v4 gnomad_v2
BS2	Not met	This variant has not been observed in homozygous state in gnomAD, so the available population data do not support observation in healthy individuals sufficient for BS2.	gnomad_v2 gnomad_v4
BS3	Not assessed	No well-established functional study showing a normal or benign effect for p.Arg540Cys was identified.	oncokb PMID:32051609
BS4	Not assessed	No data were identified showing lack of segregation of this variant with disease in a family.	clinvar
BP1	Not assessed	Although CTNNA1 loss of function is an established disease mechanism, the available materials do not support using BP1 to treat missense variation in this gene as generally benign.	pvs1_gene_context PMID:32051609
BP2	Not assessed	No phase data were identified showing this variant in trans with a pathogenic variant for a dominant disorder or in cis with a pathogenic variant in a way that would support BP2.	clinvar
BP3	N/A	BP3 applies to in-frame insertions/deletions in repetitive regions, which is not the variant type observed here.
BP4	Not met	Available computational evidence does not provide consistent support for a benign effect. SpliceAI is neutral for splicing (max delta score 0.00), but REVEL 0.305 and BayesDel 0.105968 are not sufficiently benign to support BP4.	spliceai revel bayesdel
BP5	Not assessed	No alternate molecular explanation was identified that would clearly account for the phenotype independently of this variant.	clinvar
BP6	Not met	No reputable source classified this variant as benign or likely benign. Available ClinVar submissions classify it as uncertain significance.	clinvar
BP7	N/A	BP7 applies to synonymous or certain intronic variants without predicted splice impact, which is not the variant type observed here.

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.