NM_000719.7:c.5779C>G

CACNA1C · NP_000710.5:p.(His1927Asp) · NM_000719.7

GRCh37: chr12:2795430 C>G · GRCh38: chr12:2686264 C>G

Gene: CACNA1C Transcript: NM_000719.7

Final call

VUS

PM2 supporting BP4 supporting benign

Variant details

Gene

CACNA1C

Transcript

NM_000719.7

Protein

NP_000710.5:p.(His1927Asp)

gnomAD AF

2.489330108821066e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_000719.7:c.5779C>G (p.His1927Asp) in CACNA1C is a missense variant in exon 45 classified as Uncertain significance in ClinVar (VariationID 1481507, 2 clinical laboratories).

This variant is absent from gnomAD v2.1 and present at extremely low frequency in gnomAD v4.1 (AF=0.00025%, 4/1,606,858 alleles, 0 homozygotes; grpmax FAF=8e-7), well below the 0.1% PM2 threshold for population rarity (PM2_Supporting).

Multiple in silico tools suggest no deleterious impact: SpliceAI predicts no splicing effect (max delta 0.02) and BayesDel score (0.079) falls in the benign range; REVEL score (0.378) is intermediate and below established pathogenic thresholds (BP4_Supporting).

No functional studies, case-control data, segregation analysis, de novo observations, or same-residue pathogenic comparators were identified in the reviewed literature or ClinVar submissions.

Four publications cited in ClinVar were reviewed: a GeneReviews overview (PMID:20301308), an expert consensus statement on inherited arrhythmias (PMID:23994779), the ACMG SF v3.1 policy statement (PMID:35802134), and the Sherloc variant classification framework (PMID:28492532). None of these publications mention or study this specific variant.

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 substitution (c.5779C>G, p.His1927Asp), not a null variant (nonsense, frameshift, or canonical splice site). The PVS1 null-variant framework is not applicable to missense variants.	pvs1_variant_assessment
PS1	Not met	No evidence that a different nucleotide substitution at codon His1927 has been classified as pathogenic. PS1 requires a known pathogenic variant at the same amino acid position via a different nucleotide change.	clinvar
PS2	Not met	No confirmed de novo occurrence reported for this variant in any publication or ClinVar submission.
PS3	Not met	No well-established functional studies demonstrating a deleterious effect for this variant have been identified. In silico scores (REVEL 0.378, BayesDel 0.079) do not constitute functional evidence.
PS4	Not met	No case-control studies demonstrate statistically significant enrichment of this variant in affected individuals. Reviewed publications are gene-level guidelines or classification framework papers that do not report case observations for this variant.
PS5	Not met	No evidence of this variant found in trans with a known pathogenic variant for a recessive disorder. CACNA1C-associated disorders are typically autosomal dominant.
PM1	Not met	Residue His1927 is not located within a statistically significant mutational hotspot in CACNA1C. The variant lies in the C-terminal region (exon 45 of 47), distal to established functional domains.
PM2	Met	This variant is absent from gnomAD v2.1 and present at extremely low frequency in gnomAD v4.1 (AF=0.00025%, 4/1,606,858 alleles, 0 homozygotes; grpmax FAF=8e-7), well below the 0.1% PM2 threshold. Also absent from gnomAD-Canada v1.0.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	Unable to confirm classic same-residue PM5 comparator semantics; no same-residue candidate variants with established pathogenicity were identified.	pm5_candidates
PM6	Not met	No de novo observations (with or without confirmed paternity/maternity) have been reported for this variant.
PP1	Not met	No co-segregation data available for this variant in affected families.
PP2	Not met	Insufficient constraint data to establish that CACNA1C has a low rate of benign missense variation. Missense constraint metrics (e.g., Z-score) are not available in the evidence packet for this gene.
PP3	Not met	In silico predictions do not support a deleterious effect: REVEL score 0.378 is below the typical pathogenic threshold (>0.5), BayesDel score 0.079 is in the benign range, and SpliceAI predicts no splicing impact (max delta 0.02).	revel bayesdel spliceai
PP4	Not met	No phenotype or family history data are available for individuals carrying this variant. PP4 requires phenotype highly specific for a disease with a single genetic etiology.
PP5	Not met	No reputable source reports this variant as pathogenic. ClinVar classification is Uncertain significance (2 clinical laboratories, criteria provided, single submitter). The cited ClinVar publications are gene-level reviews or classification frameworks that do not implicate this variant as pathogenic.	clinvar
BA1	Not met	Allele frequency in gnomAD v4.1 is 0.00025% (4/1,606,858), far below the 1% BA1 threshold.	gnomad_v4
BS1	Not met	Allele frequency in gnomAD v4.1 is 0.00025% (4/1,606,858), below the 0.3% BS1 threshold for a dominant disorder.	gnomad_v4
BS2	Not met	No evidence that this variant has been observed in healthy adult controls with full penetrance data. While 4 alleles are present in gnomAD, gnomAD does not provide phenotype confirmation of healthy status for a fully penetrant early-onset disorder.
BS3	Not met	No well-established functional studies demonstrate no deleterious effect for this variant.
BS4	Not met	No segregation data available to demonstrate lack of co-segregation with disease.
BP1	Not met	While CACNA1C loss-of-function is a supported disease mechanism, missense variants are also a well-established pathogenic mechanism in this gene (e.g., p.Gly406Arg causing Timothy syndrome). BP1 is applicable only when truncating variants are the sole disease mechanism, which is not the case for CACNA1C.	pvs1_gene_context
BP2	Not met	No evidence of this variant observed in trans with a pathogenic variant in a dominant disorder.
BP4	Met	Multiple in silico tools suggest no deleterious impact: SpliceAI predicts no splicing effect (max delta 0.02), and BayesDel score (0.079) is in the benign range below standard pathogenic thresholds. REVEL score (0.378) is intermediate and below the established pathogenic threshold (>0.5).	revel bayesdel spliceai
BP5	Not met	No evidence of an alternate molecular basis for disease in individuals carrying this variant.
BP6	Not met	No reputable source classifies this variant as benign. ClinVar classification is Uncertain significance.	clinvar
BP7	N/A	This is a missense variant (p.His1927Asp), not a synonymous or intronic variant outside splice sites.

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.