CTNNA1 c.1193A>G, p.(Asn398Ser)

Reasoning

The variant is missense (NP_001894.2:p.(Asn398Ser)), so the applicable computational path is REVEL only. REVEL is 0.079, meeting the supplied ClinGen SVI BP4 supporting threshold of <=0.29 from Pejaver et al. 2022 (PMID:36413997). The SpliceAI max delta of 0.047 is not used because splice prediction cannot provide BP4 support for a missense variant, and BayesDel has no established generic ACMG strength calibration.

Evidence considered

• The normalized consequence is missense, NP_001894.2:p.(Asn398Ser), so REVEL is the sole applicable PP3/BP4 path.
• REVEL score is 0.079, meeting the supplied ClinGen SVI BP4 supporting threshold <=0.29 (Pejaver et al. 2022, PMID:36413997).
• SpliceAI and BayesDel were not used for this missense BP4 assessment; BayesDel has no generic ACMG-strength calibration.

Sources

Reasoning

Generic ACMG/AMP is applicable because no CTNNA1-specific VCEP or CSPEC framework was available. The supplied generic PM2 threshold is allele frequency at most 0.0001. Using the required default all-comers population totals, gnomAD v2.1 reports AF 0.000103222 (29/280,948 alleles) and gnomAD v4.1 reports AF 0.000132166 (213/1,611,606 alleles); both exceed 0.0001, so PM2 is not met. The gnomAD v2.1 exome-only AF is 0.0000881601 and would fall below the threshold, but no governing specification requires that exome-only or non-cancer subset, so it does not replace the default all-comers assessment.

Rule

{'source': 'generic_acmg', 'threshold': 'allele frequency <= 0.0001', 'threshold_publication': 'PMID:25741868', 'population_source': 'default all-comers gnomAD v2.1 and v4.1; non-cancer or exome-only subset not mandated'}

Evidence considered

• gnomAD v4.1 all-comers AF is 0.000132166 (213/1,611,606 alleles), with zero homozygotes.
• gnomAD v2.1 all-comers AF is 0.000103222 (29/280,948 alleles), with zero homozygotes; the exome-only AF is 0.0000881601 (22/249,546 alleles).
• The supplied generic SVI PM2 threshold is AF <= 0.0001 (ClinGen SVI recommendation, PMID:25741868). The exome-only v2.1 value would meet this threshold, but no governing VCEP specification requires that subset, so the default all-comers totals control.

Sources

Reasoning

The variant is missense (NP_001894.2:p.(Asn398Ser)), so the applicable computational path is REVEL only. REVEL is 0.079, which does not meet any PP3 threshold: >=0.644 supporting, >=0.773 moderate, or >=0.932 strong, using the supplied ClinGen SVI calibration from Pejaver et al. 2022 (PMID:36413997). The SpliceAI max delta of 0.047 is not evaluated for PP3 because splice prediction cannot support a missense PP3 assessment, and BayesDel has no established generic ACMG strength calibration.

Evidence considered

• The normalized consequence is missense, NP_001894.2:p.(Asn398Ser), so REVEL is the sole applicable PP3/BP4 path.
• REVEL score is 0.079; the supplied ClinGen SVI thresholds are PP3 supporting >=0.644, moderate >=0.773, and strong >=0.932 (Pejaver et al. 2022, PMID:36413997).
• SpliceAI and BayesDel were not used for this missense PP3 assessment; BayesDel has no generic ACMG-strength calibration.

Sources

Reasoning

PP5 is restricted here to an exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification. ClinVar shows 0 expert-panel submissions for NM_001903.5:c.1193A>G (p.Asn398Ser); the available exact-variant classifications are ordinary laboratory submissions, including Likely benign, Benign, and Uncertain significance. Therefore PP5 is not met.

Rule

Apply PP5 only when an exact-variant ClinVar expert panel classifies the variant as Pathogenic or Likely pathogenic; ordinary laboratory submissions, aggregate labels, and non-expert assertions do not qualify.

Evidence considered

• ClinVar submission audit reports an exact transcript-HGVS match and 0 expert-panel submissions.
• The exact-variant submission summary contains 5 Uncertain significance, 1 Benign, and 1 Likely benign laboratory classifications; none is an expert-panel Pathogenic or Likely pathogenic assertion.
• Ordinary laboratory submissions and aggregate ClinVar labels were excluded from PP5 by rule.

Sources

Reasoning

Generic ACMG/AMP is applicable because no CTNNA1-specific VCEP or CSPEC framework was available. BA1 requires an allele frequency of at least 0.05. The highest reported all-comers population frequency is 0.000467065 in the gnomAD v4.1 African/African American subgroup, and the overall gnomAD v4.1 frequency is 0.000132166 (213/1,611,606 alleles); gnomAD v2.1 is also far below the threshold at 0.000103222 overall (29/280,948 alleles). Therefore BA1 is not met. No non-cancer-specific source was specified by a governing framework, so the all-comers totals are the applicable default.

Rule

{'source': 'generic_acmg', 'threshold': 'allele frequency >= 0.05', 'threshold_publication': 'PMID:25741868', 'population_source': 'all-comers gnomAD v2.1 and v4.1; no governing non-cancer or exome-only specification available'}

Evidence considered

• gnomAD v4.1 reports an overall allele frequency of 0.000132166 (213/1,611,606 alleles) and a highest subgroup frequency of 0.000467065 in African/African American individuals.
• gnomAD v2.1 reports an overall allele frequency of 0.000103222 (29/280,948 alleles); its highest reported subgroup frequency is 0.000442336.
• The generic ACMG/AMP stand-alone benign frequency threshold is AF >= 0.05 (ACMG/AMP 2015, PMID:25741868).

Sources

Reasoning

Generic ACMG/AMP is applicable because no CTNNA1-specific VCEP or CSPEC framework was available. The supplied generic BS1 threshold is allele frequency at least 0.01. The highest observed frequency is 0.000467065 in the gnomAD v4.1 African/African American subgroup; the overall gnomAD v4.1 frequency is 0.000132166 and the gnomAD v2.1 overall frequency is 0.000103222. All are below 0.01, so BS1 is not met. No governing framework specifies a non-cancer or exome-only source, therefore the all-comers totals are the applicable default.

Rule

{'source': 'generic_acmg', 'threshold': 'allele frequency >= 0.01', 'threshold_publication': 'PMID:28518168', 'population_source': 'all-comers gnomAD v2.1 and v4.1; no governing non-cancer or exome-only specification available'}

Evidence considered

• gnomAD v4.1 reports an overall allele frequency of 0.000132166 and a highest subgroup frequency of 0.000467065 in African/African American individuals.
• gnomAD v2.1 reports an overall allele frequency of 0.000103222 and a highest reported subgroup frequency of 0.000442336.
• The supplied generic SVI BS1 calibration is AF >= 0.01, with per-gene derivation preferred (Whiffin et al. 2017, PMID:28518168).

Sources

Reasoning

Generic ACMG/AMP is applicable because no CTNNA1-specific VCEP or CSPEC framework was available. BS2 requires observation of the variant in healthy adults, typically including healthy homozygotes when the disorder is fully penetrant and the inheritance model makes that observation informative. The available gnomAD v2.1 and v4.1 data show zero homozygotes, so the required benign observation is absent; presence of heterozygous alleles alone does not establish BS2. The available population data therefore do not meet BS2.

Rule

{'source': 'generic_acmg', 'requirement': 'observation in healthy adults; informative healthy homozygotes where applicable', 'threshold_publication': 'PMID:25741868', 'population_source': 'all-comers gnomAD v2.1 and v4.1'}

Evidence considered

• gnomAD v2.1 reports 0 homozygotes in 280,948 alleles, and gnomAD v4.1 reports 0 homozygotes in 1,611,606 alleles.
• The variant is present heterozygously in population databases, but heterozygous observations alone do not satisfy the BS2 requirement for an informative healthy-individual observation.
• ACMG/AMP 2015 defines BS2 as observation in healthy adults, including healthy homozygotes where relevant to the disorder and inheritance model (PMID:25741868).

Sources

Reasoning

BP6 is restricted here to an exact-variant ClinVar expert-panel Benign or Likely benign classification. ClinVar shows 0 expert-panel submissions; the exact-variant Benign and Likely benign assertions are single-submitter clinical-laboratory submissions. Those non-expert assertions cannot trigger BP6, so BP6 is not met.

Rule

Apply BP6 only when an exact-variant ClinVar expert panel classifies the variant as Benign or Likely benign; ordinary laboratory submissions, aggregate labels, and non-expert assertions do not qualify.

Evidence considered

• ClinVar submission audit reports an exact transcript-HGVS match and 0 expert-panel submissions.
• The exact-variant Benign and Likely benign classifications are identified as ordinary clinical-laboratory single-submitter submissions, not expert-panel assertions.
• Aggregate ClinVar labels and non-expert assertions were excluded from BP6 by rule.

Sources

Still missing

• attempt 1: evidence_refs must contain only source_registry keys
• attempt 2: evidence_refs must contain only source_registry keys
• attempt 3: evidence_refs must contain only source_registry keys

Reasoning

No variant-specific evidence establishes that CTNNA1 c.1193A>G (p.Asn398Ser) is de novo in a proband. The available case and literature records do not document parental genotypes, confirmed maternity and paternity, or a relevant de novo observation, so PS2 cannot be applied.

Rule

Generic ACMG/AMP PS2: de novo occurrence in a patient with the disease and no family history, with maternity and paternity confirmed; apply only when variant-specific parental testing supports de novo status.

Evidence considered

• The available records identify CTNNA1 c.1193A>G (p.Asn398Ser) but contain no variant-specific parental testing or confirmed de novo result.
• The reviewed literature extracts for PMID:27153395 and PMID:32051609 do not report this exact variant with de novo or parental-genotype evidence.

Still missing

• Variant-specific proband record identifying the phenotype and testing context
• Maternal and paternal genotype results for c.1193A>G
• Confirmation of maternity and paternity
• Independent confirmation that the variant is absent from both parents

Sources

Reasoning

No variant-specific validated functional assay evidence was identified for CTNNA1 NM_001903.5:c.1193A>G (p.Asn398Ser). The exact-variant literature trail includes papers reporting clinical testing or general ACMG classification, but the reviewed extracts contain no experimental assay of this substitution, no assay controls, no quantitative functional result, and no evidence establishing a disease-relevant functional effect. Therefore PS3 cannot be applied at any strength under the generic ACMG/AMP framework.

Rule

Generic ACMG/AMP PS3 requires well-established functional studies appropriate to the disease mechanism; no qualifying variant-specific study was identified.

Evidence considered

• ClinVar records the exact NM_001903.5:c.1193A>G (p.Asn398Ser) variant, but the usable submission trail provides no PS3 assertion or variant-specific functional assay result.
• PMID:27153395 describes ACMG-based classification of many germline variants and does not report a functional assay for CTNNA1 p.Asn398Ser.
• PMID:32051609 reports CTNNA1 multigene-panel testing and missense VUS counts but does not report a functional assay for p.Asn398Ser.
• No CTNNA1-specific VCEP or gene-specific functional calibration was available, so generic ACMG/AMP criteria apply.

Still missing

• A validated disease-relevant functional assay testing CTNNA1 p.Asn398Ser is unavailable or not documented.
• Assay controls, quantitative results, and a prespecified PS3 strength calibration are unavailable.

Sources

Reasoning

No case-control enrichment, odds ratio, statistically supported excess of the exact NM_001903.5:c.1193A>G variant in affected individuals, or sufficiently documented affected-case series was identified. The available literature extracts do not mention CTNNA1 c.1193A>G or p.Asn398Ser, so PS4 cannot be applied.

Rule

Generic ACMG/AMP PS4 requires a significantly increased prevalence of the variant in affected individuals compared with controls; no VCEP-specific CTNNA1 rule was available.

Evidence considered

• No case-control counts, odds ratio, confidence interval, or exact-variant prevalence estimate was provided for NM_001903.5:c.1193A>G.
• PMID:27153395 and PMID:32051609 were checked through their extracted findings; neither reports the exact CTNNA1 c.1193A>G (p.Asn398Ser) variant.

Still missing

• An exact-variant case-control dataset or adequately documented affected-case series is unavailable.

Sources

Still missing

• attempt 1: evidence_refs must contain only source_registry keys
• attempt 2: evidence_refs must contain only source_registry keys
• attempt 3: evidence_refs must contain only source_registry keys

Reasoning

No CTNNA1-specific VCEP or gene framework is available, so the generic ACMG/AMP PM3 rule applies: PM3 requires the assessed variant to be observed in trans with a pathogenic or likely pathogenic variant in an affected individual for a recessive disorder, with strength based on the number and quality of independent observations. The available case evidence identifies NM_001903.5:c.1193A>G (p.Asn398Ser) as a missense variant but provides no affected-proband observation, no second pathogenic variant, no phasing result, and no inheritance information. Therefore, PM3 cannot be assessed and no strength can be assigned.

Rule

generic_acmg_pm3_requires_pathogenic_variant_in_trans_in_an_affected_individual; strength_requires_validated_observation_count

Evidence considered

• The ClinVar record reports aggregate submissions and classifications for NM_001903.5:c.1193A>G (p.Asn398Ser), but no affected individual, second pathogenic variant, phase, or inheritance observation is provided.
• No CTNNA1-specific VCEP or gene-specific framework is available; generic ACMG/AMP PM3 guidance was therefore used.

Still missing

• Affected-proband-level data are needed.
• A second pathogenic or likely pathogenic variant and confirmed trans phase are needed for PM3.
• The relevant CTNNA1 inheritance model is not established in the available case evidence.

Sources

Still missing

• attempt 1: evidence_refs must contain only source_registry keys
• attempt 2: evidence_refs must contain only source_registry keys
• attempt 3: evidence_refs must contain only source_registry keys

Reasoning

No variant-specific report supports an assumed de novo occurrence of CTNNA1 c.1193A>G (p.Asn398Ser) without confirmed maternity and paternity. Because neither a proband de novo observation nor the family-history context is documented, PM6 cannot be applied.

Rule

Generic ACMG/AMP PM6: assumed de novo occurrence in a patient with the disease and no family history, without confirmation of maternity and paternity; apply only when the case report supports the assumption.

Evidence considered

• The available records contain no variant-specific report describing CTNNA1 c.1193A>G as assumed de novo.
• The reviewed literature extracts for PMID:27153395 and PMID:32051609 do not provide an exact-variant de novo observation or relevant family-history evidence.

Still missing

• Variant-specific proband and phenotype information
• Documented family-history context
• Parental testing or a report explicitly describing assumed de novo status
• Assessment of maternity and paternity confirmation

Sources

Reasoning

No variant-specific segregation series is available for CTNNA1 c.1193A>G (p.Asn398Ser). The records do not identify informative affected or unaffected relatives carrying or lacking the variant, provide meioses, or establish phenotype concordance; therefore PP1 cannot be applied.

Rule

Generic ACMG/AMP PP1: cosegregation with disease in multiple affected family members; strength depends on the number and informativeness of meioses and the phenotype, and requires variant-specific segregation data.

Evidence considered

• The available records do not report family members tested for CTNNA1 c.1193A>G or any count of informative meioses.
• PMID:27153395 evaluated many germline variants in families but its extraction does not report CTNNA1 c.1193A>G or variant-specific segregation data.
• PMID:32051609 reports CTNNA1 missense VUS observations without variant-specific segregation evidence for p.(N398S).

Still missing

• Pedigree with affected and unaffected relatives
• Genotypes for informative relatives
• Number of informative meioses
• Phenotype assessment and concordance for each tested relative

Sources

Still missing

• attempt 1: evidence_refs must contain only source_registry keys
• attempt 2: evidence_refs must contain only source_registry keys
• attempt 3: evidence_refs must contain only source_registry keys

Reasoning

No individual-level phenotype, diagnostic findings, or phenotype specificity assessment for the variant carrier was supplied. Gene-level descriptions of hereditary diffuse gastric cancer or other conditions cannot establish that this variant caused a highly specific phenotype, so PP4 cannot be applied.

Rule

Generic ACMG/AMP PP4 requires a phenotype or highly specific disease finding that is highly specific for a disease with a single-gene etiology; no VCEP-specific CTNNA1 rule was available.

Evidence considered

• The case materials contain no exact-variant carrier phenotype, clinical presentation, or disease-specific diagnostic finding suitable for PP4.

Still missing

• A documented phenotype and disease-specific diagnostic assessment for an exact-variant carrier are unavailable.

Sources

Reasoning

No variant-specific validated functional assay evidence was identified for CTNNA1 NM_001903.5:c.1193A>G (p.Asn398Ser). The reviewed exact-variant literature extracts contain no normal-function assay result, appropriate positive and negative controls, quantitative measurement, or disease-relevant assay validation demonstrating that this substitution is functionally benign. Therefore BS3 cannot be applied at any strength under the generic ACMG/AMP framework.

Rule

Generic ACMG/AMP BS3 requires well-established functional studies showing no damaging effect and appropriate assay validation; no qualifying variant-specific study was identified.

Evidence considered

• ClinVar records the exact NM_001903.5:c.1193A>G (p.Asn398Ser) variant, but the usable submission trail provides no BS3 assertion or variant-specific functional assay result.
• PMID:27153395 describes ACMG-based classification of many germline variants and does not report a normal-function assay for CTNNA1 p.Asn398Ser.
• PMID:32051609 reports CTNNA1 multigene-panel testing and missense VUS counts but does not report a normal-function assay for p.Asn398Ser.
• No CTNNA1-specific VCEP or gene-specific functional calibration was available, so generic ACMG/AMP criteria apply.

Still missing

• A validated disease-relevant functional assay showing preserved CTNNA1 p.Asn398Ser function is unavailable or not documented.
• Assay controls, quantitative results, and a prespecified BS3 strength calibration are unavailable.

Sources

Reasoning

No variant-specific non-segregation evidence is documented for CTNNA1 c.1193A>G (p.Asn398Ser). The available records do not show affected relatives who lack the variant despite adequate testing and phenotype assessment, so BS4 cannot be applied.

Rule

Generic ACMG/AMP BS4: lack of segregation in affected members of a family; apply only when affected relatives are adequately phenotyped and tested and the negative genotype is informative.

Evidence considered

• The available records contain no variant-specific family study documenting affected relatives who tested negative for CTNNA1 c.1193A>G.
• The reviewed literature extracts for PMID:27153395 and PMID:32051609 do not provide exact-variant non-segregation evidence.

Still missing

• Affected relatives with reliable clinical phenotyping
• Genotype results demonstrating absence of c.1193A>G in those relatives
• Adequate segregation study design and informative meioses
• Assessment of phenocopy and age-related disease penetrance

Sources

Still missing

• attempt 1: evidence_refs must contain only source_registry keys
• attempt 2: evidence_refs must contain only source_registry keys
• attempt 3: evidence_refs must contain only source_registry keys

Reasoning

No CTNNA1-specific VCEP or gene framework is available, so the generic ACMG/AMP BP2 rule applies: BP2 requires observation of the assessed variant in trans with a pathogenic or likely pathogenic variant for a dominant disorder, or in cis with a pathogenic or likely pathogenic variant for a recessive disorder. The available case evidence contains no affected-proband or family-level genotype data, no second pathogenic or likely pathogenic variant, and no cis/trans phase information. Because neither the required allelic observation nor the inheritance context is documented, BP2 cannot be assessed.

Rule

generic_acmg_bp2_requires_pathogenic_variant_in_trans_for_dominant_disorder_or_in_cis_for_recessive_disorder

Evidence considered

• The ClinVar record reports aggregate submissions and classifications for NM_001903.5:c.1193A>G (p.Asn398Ser), but no family-level genotype, second pathogenic variant, or cis/trans phase observation is provided.
• No CTNNA1-specific VCEP or gene-specific framework is available; generic ACMG/AMP BP2 guidance was therefore used.

Still missing

• Family or affected-proband genotype data are needed.
• A pathogenic or likely pathogenic allele and confirmed cis/trans phase are needed for BP2.
• The relevant CTNNA1 inheritance model is not established in the available case evidence.

Sources

Reasoning

No documented affected individual with an alternate molecular explanation for the relevant phenotype, and no appropriately matched alternate pathogenic variant, was supplied for this exact-variant case. The presence of a single-submitter ClinVar Likely benign assertion is not BP5 evidence, so BP5 cannot be applied.

Rule

Generic ACMG/AMP BP5 requires the variant to be found in an affected individual with an alternative molecular basis for the disease; no VCEP-specific CTNNA1 rule was available.

Evidence considered

• The available ClinVar record contains laboratory classifications but no affected-case evidence demonstrating an alternate molecular cause.
• No case report or segregation record documents the exact variant in an individual whose phenotype is explained by another pathogenic variant.

Still missing

• An affected case with a confirmed alternate molecular cause and appropriate phenotype matching is unavailable.

Sources