CTNNA1 c.710A>G, p.(Tyr237Cys)

Reasoning

The variant is extremely rare in population databases and no homozygotes are observed. gnomAD v4.1 reports AF 4.83236e-05 overall and 2.49975e-04 in the highest-frequency population; gnomAD v2.1 reports AF 8.75065e-05 overall and 3.46901e-04 in the highest-frequency population. These values are below the generic rare-variant cutoff of 0.1%, supporting PM2 at supporting strength. gnomAD-Canada v1.0 was unavailable and therefore does not alter the assessment.

Rule

Generic PM2: absent or rare in population databases; operational threshold used here is AF <0.1%, with supporting strength for this rare but observed allele.

Evidence considered

• gnomAD v4.1: AF 4.83236e-05 (78/1,614,118 alleles), highest population AF 2.49975e-04 in Admixed Americans, and 0 homozygotes.
• gnomAD v2.1: AF 8.75065e-05 (22/251,410 alleles), highest population AF 3.46901e-04 in Admixed Americans, and 0 homozygotes.
• gnomAD-Canada v1.0 was not available for this variant because the queried record was absent/timeout-limited; this is a data gap, not evidence of absence.
• No applicable CTNNA1 VCEP or CSPEC specification was available; generic PM2 rare-frequency criteria were used.

Still missing

• No CTNNA1-specific VCEP/CSPEC PM2 threshold or disease-specific maximum credible allele frequency was available.

Sources

Reasoning

Not met. CTNNA1 c.710A>G is a missense variant, NM_001903.5(NP_001894.2):p.(Tyr237Cys), so the generic missense REVEL path is the sole applicable computational-evidence mechanism. No governing CTNNA1 VCEP/CSPEC or local gene-specific PP3/BP4 rule was available. REVEL is 0.278, which is below the PP3 threshold of >0.750.

Rule

Generic ACMG/AMP missense computational-evidence fallback: REVEL >0.750 supports PP3 at supporting strength (calibration: PMID:36413997).

Evidence considered

• The case normalization identifies NM_001903.5:c.710A>G as NP_001894.2:p.(Tyr237Cys), a missense substitution; therefore SpliceAI was not used to adjudicate PP3.
• Local REVEL lookup reports 0.278 for the variant. Under the applicable generic calibrated REVEL rule, PP3 requires REVEL >0.750; the calibration publication is PMID:36413997.
• No CTNNA1 VCEP/CSPEC, gene-specific PP3/BP4 lookup, or other governing framework was supplied; generic ACMG/AMP computational calibration applies.

Sources

Reasoning

PP5 is not met because the exact ClinVar record has no expert-panel submission classified Pathogenic or Likely pathogenic. The record contains only single-submitter laboratory assertions, predominantly uncertain significance, which cannot trigger PP5.

Rule

Apply PP5 only to an exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification; ordinary laboratory submissions and aggregate labels do not qualify.

Evidence considered

• The ClinVar submission audit confirms an exact-variant match and zero expert-panel submissions.

Sources

Reasoning

The variant is far below the generic standalone benign population-frequency threshold. gnomAD v4.1 reports AF 4.83236e-05 (78/1,614,118 alleles), with the highest reported population AF 2.49975e-04 in Admixed Americans; gnomAD v2.1 reports AF 8.75065e-05 and highest population AF 3.46901e-04. These frequencies do not meet a BA1 threshold of >1%.

Rule

Generic BA1: allele frequency >1% is required for standalone benign evidence; observed frequencies are substantially lower.

Evidence considered

• gnomAD v4.1: total AF 4.83236e-05 (78/1,614,118 alleles), zero homozygotes, highest population AF 2.49975e-04 in Admixed Americans.
• gnomAD v2.1: total AF 8.75065e-05 (22/251,410 alleles), zero homozygotes, highest population AF 3.46901e-04 in Admixed Americans.
• No applicable CTNNA1 VCEP or CSPEC specification was available; generic population-frequency thresholds were used.

Sources

Reasoning

The observed population frequency is not greater than expected for a pathogenic CTNNA1 variant under the generic threshold used here. The maximum reported population AF is 2.49975e-04 in gnomAD v4.1 (3.46901e-04 in gnomAD v2.1), below 0.3%; therefore BS1 is not met.

Rule

Generic BS1: allele frequency greater than expected for the disorder; operational threshold used here is >0.3% in a population database.

Evidence considered

• gnomAD v4.1: total AF 4.83236e-05; highest population AF 2.49975e-04 in Admixed Americans; zero homozygotes.
• gnomAD v2.1: total AF 8.75065e-05; highest population AF 3.46901e-04 in Admixed Americans; zero homozygotes.
• No CTNNA1-specific disease prevalence, penetrance, or maximum credible allele-frequency threshold was provided, so the generic BS1 threshold of >0.3% was applied.

Sources

Reasoning

BS2 is not met. gnomAD v4.1 and v2.1 report zero homozygotes for the variant, and the bundle provides no phenotype-confirmed healthy-adult observations. Presence of heterozygous alleles in an ostensibly population-based database alone does not establish the ACMG/AMP BS2 observation in healthy individuals, particularly without ascertainment, age, phenotype, inheritance, and penetrance information.

Rule

Generic BS2: observation in healthy adults, including homozygosity for a dominant disorder where applicable, must be established; population-database allele presence without phenotype ascertainment is insufficient.

Evidence considered

• gnomAD v4.1 reports 0 homozygotes among 1,614,118 alleles; gnomAD v2.1 reports 0 homozygotes among 251,410 alleles.
• The available population records provide allele counts and homozygote counts but do not establish that identified carriers are healthy adults with adequate phenotypic assessment.
• The generic ACMG/AMP guidance was consulted for the population-evidence framework; no variant-specific CTNNA1 observation was reported.

Still missing

• No phenotype-confirmed healthy-adult carriers or disease-specific penetrance analysis was provided.
• No CTNNA1-specific BS2 specification was available.

Sources

Reasoning

Not met. CTNNA1 c.710A>G is a missense variant, NM_001903.5(NP_001894.2):p.(Tyr237Cys), so the generic missense REVEL path is the sole applicable computational-evidence mechanism. No governing CTNNA1 VCEP/CSPEC or local gene-specific PP3/BP4 rule was available. REVEL is 0.278, which is above the BP4 threshold of <0.250 and falls in the 0.250-0.750 gray zone.

Rule

Generic ACMG/AMP missense computational-evidence fallback: REVEL <0.250 supports BP4 at supporting strength; REVEL 0.250-0.750 meets neither PP3 nor BP4 (calibration: PMID:36413997).

Evidence considered

• The case normalization identifies NM_001903.5:c.710A>G as NP_001894.2:p.(Tyr237Cys), a missense substitution; SpliceAI 0.011 was deliberately not used because absence of predicted splice impact is not evidence about the substituted amino acid.
• Local REVEL lookup reports 0.278 for the variant. Under the applicable generic calibrated REVEL rule, BP4 requires REVEL <0.250; values from 0.250 through 0.750 are indeterminate. The calibration publication is PMID:36413997.
• The available BayesDel score was not used because no verified published BayesDel calibration threshold is available for this pipeline.

Sources

Reasoning

BP6 is not met because the exact ClinVar record has no expert-panel submission classified Benign or Likely benign. One benign assertion is from a single clinical laboratory and cannot trigger BP6.

Rule

Apply BP6 only to an exact-variant ClinVar expert-panel Benign or Likely benign classification; ordinary laboratory submissions and aggregate labels do not qualify.

Evidence considered

• The ClinVar submission audit confirms an exact-variant match and zero expert-panel submissions; the benign assertion is a single-submitter laboratory classification.

Sources

Reasoning

The variant is CTNNA1 NM_001903.5:c.710A>G (NP_001894.2:p.(Tyr237Cys)), but the case bundle contains no confirmed pathogenic or likely pathogenic variant producing the same amino-acid change. The available paper extractions do not report CTNNA1 or this variant, and ClinVar is not an expert-panel source for establishing PS1.

Rule

PS1 requires a well-established pathogenic variant resulting in the same amino-acid change; no qualifying comparator was established in this case.

Evidence considered

• The case variant is p.Tyr237Cys.
• The extracted full-text papers in the bundle do not mention CTNNA1 or p.Tyr237Cys.
• The ClinVar record is classified as uncertain significance with criteria provided by single submitters and has no expert-panel submission.

Still missing

• A validated pathogenic or likely pathogenic same-amino-acid comparator at Tyr237 is needed.
• Variant-specific literature or a curated clinical database record supporting the comparator is needed.

Sources

Reasoning

No proband-specific de novo observation or documented parental testing is provided for CTNNA1 NM_001903.5:c.710A>G (p.Tyr237Cys). PS2 cannot be assessed without confirmed absence of the variant in both biological parents and appropriate maternity/paternity confirmation.

Rule

Generic ACMG/AMP PS2 requires a confirmed de novo variant in the patient with confirmed maternity and paternity; apply only when the required parentage and parental genotype evidence are documented.

Evidence considered

• The case bundle contains no documented parental testing, trio analysis, de novo determination, or proband-specific segregation data for this variant.
• The available literature extraction contains no CTNNA1 or c.710A>G-specific clinical or segregation observation.

Still missing

• Proband-level clinical record and phenotype consistency are not provided.
• Results of parental variant testing are not provided.
• Maternity/paternity confirmation and testing methodology are not provided.

Sources

Reasoning

No variant-specific validated functional assay evidence was identified for CTNNA1 c.710A>G (p.Tyr237Cys). The available paper extracts are general ACMG/Sherloc guidance or unrelated clinical guidelines and do not report an assay, controls, or biological effect for this variant. Therefore PS3 cannot be applied or calibrated for strength.

Rule

Generic ACMG/AMP PS3: apply only when well-established functional studies appropriate to the gene and disease mechanism show a damaging effect; strength requires calibration to assay validity, controls, reproducibility, and quantitative effect size.

Evidence considered

• The consolidated evidence bundle contains no CTNNA1-specific functional assay result for c.710A>G (p.Tyr237Cys).
• PMID:25741868 was checked via its paper extraction; it provides general missense-variant guidance but no CTNNA1 variant-specific functional data.
• PMID:28492532 was checked via its paper extraction; it provides general Sherloc rules but no CTNNA1 variant-specific functional data.
• The bundle reports no applicable CTNNA1 ClinGen/VCEP specification, so generic ACMG/AMP functional-evidence criteria were used.

Still missing

• A validated assay measuring CTNNA1 p.Tyr237Cys function is needed, with appropriate wild-type, loss-of-function or pathogenic, and benign/control comparators.
• The assay should establish biological relevance to CTNNA1 function and provide quantitative variant-specific results sufficient for PS3 strength calibration.

Sources

Reasoning

No variant-specific case-control or statistically supported enrichment data for CTNNA1 NM_001903.5:c.710A>G (p.Tyr237Cys) are present. The four fetched publications do not mention this variant or CTNNA1, and the two cohort citations (PMID:34326862 and PMID:35957908) were not available as text/full-text extractions in this case. PS4 cannot be assessed from ClinVar submissions or a single somatic COSMIC observation.

Rule

Generic ACMG/AMP PS4 requires a statistically significant increased prevalence of the variant in affected individuals compared with controls; case reports or database assertions alone are insufficient.

Evidence considered

• No CTNNA1-specific VCEP specification was retrieved; generic ACMG/AMP criteria are therefore the governing fallback.
• The pre-computed extractions for PMID:25394175, PMID:25741868, PMID:28492532, and PMID:34043773 each report that CTNNA1 c.710A>G / p.Tyr237Cys is not mentioned and provide no variant-specific clinical cohort evidence.
• ClinVar has only single-submitter laboratory assertions for this exact variant and no expert-panel submission; its assertions do not provide a case-control analysis.
• OncoKB reports no variant-specific reviewed evidence.

Still missing

• A phenotype-defined affected cohort with the number of c.710A>G carriers and an appropriate control comparison is required.
• Statistical enrichment data, including cohort ascertainment and ancestry matching, are required.
• The full text or a variant-level extraction for PMID:34326862 and PMID:35957908 is unavailable in this case.

Sources

Reasoning

No applicable CTNNA1 VCEP or gene-specific framework was available. The authoritative vcep_materials.json domain_tables object is empty, and the case bundle reports that the variant is not in a statistically significant hotspot. No independently validated critical functional domain or residue-level hotspot evidence was supplied for Tyr237, so PM1 cannot be assigned.

Rule

PM1 requires a well-established critical functional domain, mutational hotspot, or other established region in which pathogenic missense variation is concentrated and benign variation is rare; the case bundle does not establish one for Tyr237.

Evidence considered

• vcep_materials.json reports no applicable framework and an empty CTNNA1 domain_tables object; therefore there is no authoritative domain entry to check.
• The hotspot assessment states that this variant does not lie in a statistically significant hotspot.

Still missing

• A validated CTNNA1 critical functional domain or residue-level hotspot assessment covering Tyr237 is needed.
• A governing gene-specific framework, if available outside this case bundle, should be reviewed by a human adjudicator.

Reasoning

No applicable CTNNA1-specific VCEP or gene framework was available, so the generic ACMG/AMP PM3 rule was considered. The case bundle contains no affected-proband observation for this variant with a second pathogenic or likely pathogenic CTNNA1 variant, and no phasing or trans/cis information. PM3 therefore cannot be assessed.

Rule

Generic ACMG/AMP PM3: pathogenic or likely pathogenic variant observed in trans with the variant under evaluation in an affected individual, in a recessive disease context; requires reliable phase and phenotype evidence.

Evidence considered

• The governing-materials section reports no CSPEC/VCEP or gene-specific framework for CTNNA1; generic ACMG/AMP is therefore the applicable fallback.
• The case bundle identifies the variant as NM_001903.5:c.710A>G (NP_001894.2:p.(Tyr237Cys)) but provides no affected-proband, compound-heterozygous, segregation, phasing, or inheritance observation relevant to PM3.
• The extracted literature findings for PMID:25394175, PMID:25741868, PMID:28492532, and PMID:34043773 contain no CTNNA1 variant-specific allelic observations.

Still missing

• Affected-proband observations involving NM_001903.5:c.710A>G are not documented.
• A second pathogenic or likely pathogenic CTNNA1 variant is not documented in an affected individual.
• Phase and inheritance information are unavailable; trans phase is required for PM3 in a recessive context.

Sources

Reasoning

The variant changes Tyr237 to Cys, but the case bundle provides no confirmed pathogenic or likely pathogenic missense comparator at residue 237. The PM5 candidate artifact reports zero harvested same-residue candidates and explicitly states that classic PM5 semantics could not be safely confirmed; it is therefore insufficient to assign PM5 or to conclude that no qualifying comparator exists.

Rule

PM5 requires an established pathogenic missense variant at the same residue but involving a different amino-acid change; no qualifying comparator was established.

Evidence considered

• The PM5 candidate summary reports zero same-residue candidates and recommends human review rather than automatic PM5 application.
• The extracted publications do not report CTNNA1 residue-237 missense variants.

Still missing

• A curated search for different missense substitutions at CTNNA1 residue 237 is needed.
• Each comparator must have a reliable pathogenic or likely pathogenic classification independent of the target variant.

Sources

Reasoning

No report of CTNNA1 NM_001903.5:c.710A>G (p.Tyr237Cys) as apparently de novo without parental confirmation is available in the case bundle. PM6 cannot be assessed from the absence of parental information alone.

Rule

Generic ACMG/AMP PM6 is used for an apparently de novo occurrence when maternity and paternity are not confirmed; a documented patient-level de novo observation and compatible phenotype are still required.

Evidence considered

• The case bundle provides no patient-level de novo claim, family history, parental genotype result, or informative meiosis for this variant.
• The literature extraction identifies no variant-specific CTNNA1 clinical or segregation evidence.

Still missing

• A patient-level clinical report describing the variant is not provided.
• Parental testing status is not provided.
• The number of informative meioses and phenotype consistency are not provided.

Sources

Reasoning

No affected relatives carrying CTNNA1 NM_001903.5:c.710A>G (p.Tyr237Cys), unaffected relatives lacking it, or informative meioses are documented. There is therefore no basis to apply PP1 or determine its strength.

Rule

Generic ACMG/AMP PP1 requires cosegregation of the variant with disease in affected family members; strength depends on the amount and informativeness of segregation evidence.

Evidence considered

• The case bundle contains no segregation analysis, pedigree, affected-relative testing, unaffected-relative testing, or meiosis count for this variant.
• The available paper extractions do not report CTNNA1 c.710A>G or p.Tyr237Cys in a family segregation study.

Still missing

• Pedigree and family structure are not provided.
• Variant testing results for affected and unaffected relatives are not provided.
• Phenotype consistency, phase, and number of informative meioses are not provided.

Sources

Reasoning

No CTNNA1-specific framework or validated missense-enrichment evidence is available. The case bundle supports CTNNA1 loss of function as a germline disease mechanism, but does not establish that missense variants are a common disease mechanism with a low rate of benign missense variation. Therefore PP2 cannot be assigned.

Rule

PP2 requires that missense variation is a common disease mechanism for the gene and that benign missense variation is uncommon; those gene-level conditions were not established here.

Evidence considered

• The case bundle identifies CTNNA1 loss of function as a supported germline disease mechanism.
• The case bundle does not provide a validated CTNNA1-specific missense-enrichment or benign-missense-rate analysis.

Still missing

• A validated CTNNA1 missense disease mechanism assessment is needed.
• A gene-level analysis demonstrating predominance of pathogenic missense variation and rarity of benign missense variation is needed.

Reasoning

No proband phenotype, clinical diagnosis, age of onset, family history, or disease-specific testing result is provided for the carrier of CTNNA1 c.710A>G (p.Tyr237Cys). Consequently, phenotype specificity cannot be evaluated and PP4 cannot be applied.

Rule

Generic ACMG/AMP PP4 requires a patient's phenotype or family history to be highly specific for a disease with a single genetic etiology.

Evidence considered

• The case bundle contains no patient-level phenotype, clinical diagnosis, or disease-specific laboratory findings for this variant.
• No CTNNA1-specific VCEP specification was retrieved; generic ACMG/AMP criteria are therefore the governing fallback.

Still missing

• A detailed proband phenotype and confirmed diagnosis are required.
• Evidence that the phenotype is highly specific for a CTNNA1-associated disorder, including exclusion of alternative etiologies where relevant, is required.
• The relationship between this variant and any reported phenotype must be documented at the individual level.

Sources

Reasoning

No variant-specific validated functional assay demonstrating preserved CTNNA1 function was identified for c.710A>G (p.Tyr237Cys). The available paper extracts do not provide benign functional results, assay controls, or a disease-relevant experimental context. Therefore BS3 cannot be applied or calibrated for strength.

Rule

Generic ACMG/AMP BS3: apply only when well-established functional studies appropriate to the gene and disease mechanism show no damaging effect; strength requires calibration to assay validity, controls, reproducibility, and quantitative effect size.

Evidence considered

• The consolidated evidence bundle contains no CTNNA1-specific functional assay result establishing preserved function for c.710A>G (p.Tyr237Cys).
• PMID:25741868 was checked via its paper extraction; it provides general missense-variant guidance but no CTNNA1 variant-specific benign functional data.
• PMID:28492532 was checked via its paper extraction; it provides general Sherloc rules but no CTNNA1 variant-specific benign functional data.
• The bundle reports no applicable CTNNA1 ClinGen/VCEP specification, so generic ACMG/AMP functional-evidence criteria were used.

Still missing

• A validated disease-relevant assay showing preserved function for CTNNA1 p.Tyr237Cys is needed, with appropriate wild-type, pathogenic, and benign controls.
• The assay must demonstrate that the measured endpoint is biologically relevant and sufficiently quantitative and reproducible for BS3 strength calibration.

Sources

Reasoning

No affected family members reported to lack CTNNA1 NM_001903.5:c.710A>G (p.Tyr237Cys) are documented. BS4 cannot be applied without phenotype-confirmed affected relatives, reliable variant testing, and an informative family structure.

Rule

Generic ACMG/AMP BS4 requires non-segregation of the variant in affected family members; apply only after accounting for phenotype definition, age-dependent penetrance, phenocopies, and testing reliability.

Evidence considered

• The case bundle contains no documented affected non-carriers, non-segregation analysis, pedigree, or family-level phenotype/genotype data.
• The available literature extraction contains no variant-specific CTNNA1 non-segregation observation.

Still missing

• No pedigree or phenotype-confirmed affected relatives are provided.
• No genotype results for affected relatives are provided.
• Phenocopy, age-dependent penetrance, and other explanations for apparent non-segregation cannot be evaluated.

Sources

Reasoning

The available case context supports CTNNA1 loss of function as a germline disease mechanism, which is compatible with a truncating-variant-predominant disorder, but it does not establish the specific BP1 requirement that the gene's disease-causing variation is primarily truncating rather than missense. No validated gene-level BP1 framework was provided.

Rule

BP1 requires a missense variant in a gene for which primarily truncating variants cause disease; the primarily truncating pattern was not sufficiently established in this case.

Evidence considered

• The case bundle supports CTNNA1 loss of function as a germline disease mechanism.
• The case bundle does not provide a formal CTNNA1 variant-spectrum analysis or gene-specific BP1 rule.

Still missing

• A curated CTNNA1 disease-mechanism review documenting that pathogenic variation is primarily truncating is needed.
• The relevant disease context and variant spectrum should be confirmed before applying BP1.

Reasoning

No applicable CTNNA1-specific VCEP or gene framework was available, so the generic ACMG/AMP BP2 rule was considered. The case bundle contains no documented observation of this variant in trans with a pathogenic variant in a recessive context or in cis with a pathogenic variant in a dominant context. BP2 therefore cannot be assessed.

Rule

Generic ACMG/AMP BP2: variant observed in trans with a pathogenic variant for a recessive disorder, or in cis with a pathogenic variant for a dominant disorder; requires documented paired-variant and phase/inheritance evidence.

Evidence considered

• The governing-materials section reports no CSPEC/VCEP or gene-specific framework for CTNNA1; generic ACMG/AMP is therefore the applicable fallback.
• The case bundle provides no cis/trans, affected-proband, compound-heterozygous, or inheritance observation for NM_001903.5:c.710A>G.
• The extracted literature findings for PMID:25394175, PMID:25741868, PMID:28492532, and PMID:34043773 contain no CTNNA1 variant-specific allelic observations.

Still missing

• No paired pathogenic or likely pathogenic variant is documented for an affected or tested individual.
• Phase information distinguishing cis from trans is unavailable.
• The inheritance model and clinical context of any potential allele pair are not documented.

Sources

Reasoning

No individual-level molecular diagnosis explaining the reported phenotype is supplied. BP5 cannot be assessed without a documented alternate molecular cause in a person carrying CTNNA1 c.710A>G (p.Tyr237Cys).

Rule

Generic ACMG/AMP BP5 requires a variant to be found in a case with an alternate molecular basis for disease that sufficiently explains the phenotype.

Evidence considered

• The case bundle contains no proband-level phenotype, molecular diagnosis, or testing report identifying an alternate cause.

Still missing

• A proband phenotype and complete molecular testing result are required.
• A pathogenic or likely pathogenic alternate molecular diagnosis that sufficiently explains the phenotype is required.

Sources