Variant classification summary

NM_001903.5:c.*17C>T

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

GRCh37: chr5:138269795 C>T · GRCh38: chr5:138934106 C>T

Gene: CTNNA1 Transcript: NM_001903.5

Final call

VUS

Variant details

Gene

CTNNA1

Transcript

NM_001903.5

Protein

NP_001894.2:p.(=)

gnomAD AF

0.00023712605721307433 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

Final determination: Under the generic ACMG/AMP 2015 fallback, no applicable evidence combination reaches a Pathogenic, Likely Pathogenic, Likely Benign, or Benign threshold, so the variant is classified as VUS.

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	PVS1 (ClinGen SVI PVS1 recommendations, PMC6185798, pvs1_generic_framework) applies only to null variant classes — nonsense, frameshift, canonical ±1/2 splice-consensus, translation-initiation-codon loss, and stop-loss variants — each expected to trigger nonsense-mediated decay or otherwise abolish normal protein function. NM_001903.5:c.*17C>T in CTNNA1 is a synonymous (silent) substitution predicted to produce NP_001894.2:p.(=). As a result, no null-variant mechanism (nonsense-mediated decay, truncation, or canonical splice disruption) is triggered by this variant class, so PVS1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	pvs1_generic_framework generic_acmg_combination_rules
PS1	N/A	PS1 (Richards et al. 2015, PMID:25741868) requires the same amino acid change as a previously established pathogenic variant, evaluated regardless of the underlying nucleotide change. NM_001903.5:c.*17C>T in CTNNA1 is a synonymous (silent) substitution predicted to produce NP_001894.2:p.(=). As a result, no altered amino acid exists at this position to compare against any previously established pathogenic missense variant, so PS1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules
PS2	Not assessed	Not assessed: no proband phenotype, parental genotypes, maternity/paternity confirmation, or documented de novo observation is available.
PS3	Not assessed	Not assessed: no variant-specific functional assay or calibrated PS3 result was reported for CTNNA1 NM_001903.5:c.*17C>T.
PS4	Not assessed	Not assessed: no case-control enrichment, affected-case prevalence, odds ratio, or other variant-specific PS4 metric was available.	PMID:32758476 PMID:20065170 PMID:25394175
PM1	N/A	PM1 (Richards et al. 2015, PMID:25741868) applies to a missense variant located in a mutational hot spot and/or a critical, well-established functional domain without benign variation. NM_001903.5:c.*17C>T in CTNNA1 is a synonymous (silent) substitution predicted to produce NP_001894.2:p.(=). As a result, no altered residue exists to evaluate for mutational hot-spot or critical-domain membership, so PM1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules
PM2	Not met	Not met: gnomAD v4.1 allele frequency is 0.000237126, above the generic PM2 threshold of 0.0001.	gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: the documented CTNNA1 hereditary diffuse gastric cancer context is autosomal dominant, with no recessive disorder or biallelic affected-proband evidence.	PMID:32758476
PM4	N/A	PM4 (Richards et al. 2015, PMID:25741868) applies to protein length changes: in-frame insertions/deletions in a non-repetitive region, or stop-loss variants that extend the protein past the reference stop codon. NM_001903.5:c.*17C>T in CTNNA1 is a synonymous (silent) substitution predicted to produce NP_001894.2:p.(=). As a result, no change in protein length occurs, so there is nothing for this criterion to evaluate, so PM4's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	pvs1_generic_framework generic_acmg_combination_rules
PM5	N/A	PM5 (Richards et al. 2015, PMID:25741868) requires a novel missense change at an amino acid residue where a different missense change has previously been determined to be pathogenic. NM_001903.5:c.*17C>T in CTNNA1 is a synonymous (silent) substitution predicted to produce NP_001894.2:p.(=). As a result, no missense change exists at this residue to compare against a different pathogenic missense change at the same position, so PM5's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules
PM6	Not assessed	Not assessed: the case contains no reported de novo event, affected proband, or parental genotype results, whether or not parentage was confirmed.
PP1	Not assessed	Not assessed: no affected relatives, family genotypes, phenotype concordance, pedigree, or informative meioses are documented.
PP2	N/A	PP2 (Richards et al. 2015, PMID:25741868) applies to a missense variant in a gene with a low rate of benign missense variation, where missense variants are a common mechanism of disease. NM_001903.5:c.*17C>T in CTNNA1 is a synonymous (silent) substitution predicted to produce NP_001894.2:p.(=). As a result, the gene's missense-constraint properties are irrelevant because no missense change is present to evaluate, so PP2's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules
PP3	N/A	Not applicable: NM_001903.5:c.*17C>T is a downstream synonymous variant, not missense or splice-region/intronic.
PP4	Not assessed	Not assessed: no exact-variant proband phenotype or highly specific CTNNA1-related clinical presentation was documented.	PMID:32758476
PP5	Not assessed	Not assessed: ClinVar has zero expert-panel submissions and its record is a different variant, c.2472C>T rather than c.*17C>T.	clinvar
BA1	Not met	Not met: the highest reported frequency is 0.00421782, below the generic BA1 threshold of 0.05.	gnomad_v2 gnomad_v4
BS1	Not met	Not met: the highest robust group-level frequency is 0.00421782, below the generic BS1 threshold of 0.01.	gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: gnomAD v4.1 has one homozygote, but unaffected-adult status and complete CTNNA1 disease penetrance are unverified.	gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: no variant-specific functional assay or calibrated BS3 result was reported for CTNNA1 NM_001903.5:c.*17C>T.
BS4	Not assessed	Not assessed: no affected-relative phenotypes, familial genotypes, or reliable non-segregation analysis is available.
BP1	N/A	BP1 (Richards et al. 2015, PMID:25741868) applies to a missense variant in a gene for which primarily truncating variants are known to cause disease. NM_001903.5:c.*17C>T in CTNNA1 is a synonymous (silent) substitution predicted to produce NP_001894.2:p.(=). As a result, the gene's truncating-variant mechanism is irrelevant because no missense change is present to evaluate, so BP1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules
BP2	Not assessed	Not assessed: no second variant, affected-proband observation, pedigree, segregation result, or cis/trans phase determination is documented for c.*17C>T.
BP3	N/A	BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_001903.5:c.*17C>T in CTNNA1 is a synonymous (silent) substitution predicted to produce NP_001894.2:p.(=). As a result, the variant does not alter protein length within a repeat region, so there is nothing for this criterion to evaluate, so BP3's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	pvs1_generic_framework generic_acmg_combination_rules
BP4	N/A	Not applicable: NM_001903.5:c.*17C>T is a downstream synonymous variant, not missense or splice-region/intronic.
BP5	Not assessed	Not assessed: no variant-specific co-occurrence, phase, or likelihood-ratio evidence with an explanatory pathogenic variant was available.
BP6	Not assessed	Not assessed: ClinVar provides no exact-variant expert-panel Benign or Likely benign classification for c.*17C>T.	clinvar
BP7	Not assessed	Not assessed: the variant is synonymous, but SpliceAI returned no calibrated score to establish absence of splice impact.	spliceai

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