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CACNA1Cc.5779C>GUncertain significance
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Variant interpretation report

CACNA1C c.5779C>G, p.(His1927Asp)

NM_000719.7:c.5779C>G NP_000710.5:p.(His1927Asp) View identifiers
Classification
Uncertain significance

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.

Uncertain.The recorded classification is uncertain significance.

In plain language

Gene-level background from the recorded interpretation.

About CACNA1C

No gene-level summary was recorded for this case.

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.
01The reasoning

How it was classified

The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 1 Benign evidence criteria: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting

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.

Benign criteria applied · 1
BP4Supporting
BP4 · supporting

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).

Recorded classification: Uncertain significance

gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, BP4 supporting benign; combination = 1 supporting + 1 supporting benign, which maps to VUS.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

SpliceAI score
0.020 maximum delta

Recorded SpliceAI maximum delta score: 0.020. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · BP4 → SpliceAI ↗
ClinVar submissions
2 reported laboratory submissions

2 Uncertain significance. ClinVar API review status: criteria provided, multiple submitters, no conflicts.

Context only ClinVar ↗
No screenshot for this evidence
Functional evidence
Not recorded

No standalone functional evidence summary is recorded in evidence_summary.functional.

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

26 criteria with recorded statuses: 2 met · 21 not met · 0 not assessed · 3 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP4BP5BP6BP7
Met Not met Not assessed Not applicable

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.

Met · 2

PM2 SupportingThis 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. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1: absent
  • gnomAD v4.1: AF=2.49e-6 (4/1
  • 606
  • 858)
  • gnomAD-Canada: absent
Still missing
  • 4 alleles observed in gnomAD v4.1
  • all in European (non-Finnish) subpopulation.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BP4 SupportingMultiple 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). Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta=0.02 (no splicing impact)
  • BayesDel=0.079 (benign range)
  • REVEL=0.378 (intermediate
  • below pathogenic threshold >0.5)
Still missing
  • HCI prior not available for CACNA1C.
Sources
revelbayesdelspliceai ↗

Not met · 21 · evaluated, threshold not reached

PS1 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. Details ▾Hide ▴
Evidence considered
  • ClinVar contains no pathogenic variant at residue 1927 arising from a different nucleotide change.
Still missing
  • No same-residue pathogenic comparators identified.
Sources
clinvar ↗
PS2 No confirmed de novo occurrence reported for this variant in any publication or ClinVar submission. Details ▾Hide ▴
Evidence considered
  • No de novo observations in ClinVar or reviewed literature.
Still missing
  • No parental genotype data available to assess de novo status.
PS3 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. Details ▾Hide ▴
Evidence considered
  • No functional studies identified in literature or OncoKB. REVEL=0.378
  • BayesDel=0.079.
Still missing
  • No functional characterization of p.His1927Asp in any experimental system.
PS4 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. Details ▾Hide ▴
Evidence considered
  • No case observations found in ClinVar submissions or literature.
Still missing
  • No case-control data
  • no reported probands with this variant and detailed phenotype.
PM1 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. Details ▾Hide ▴
Evidence considered
  • Hotspot analysis: residue is not significant
  • exact variant not listed in hotspot database.
Still missing
  • Lack of established critical functional domain annotation for this C-terminal region.
PM6 No de novo observations (with or without confirmed paternity/maternity) have been reported for this variant. Details ▾Hide ▴
Evidence considered
  • No de novo reports in ClinVar or literature.
Still missing
  • No parental testing data available.
PP1 No co-segregation data available for this variant in affected families. Details ▾Hide ▴
Evidence considered
  • No segregation data reported.
Still missing
  • No family studies available.
PP2 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. Details ▾Hide ▴
Evidence considered
  • No missense constraint Z-score or comparable metric available for CACNA1C.
Still missing
  • No gene-level missense constraint metric in evidence.
PP3 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). Details ▾Hide ▴
Evidence considered
  • REVEL=0.378 (intermediate
  • below pathogenic threshold)
  • BayesDel=0.079 (benign range)
  • SpliceAI max delta=0.02 (no splice impact)
Sources
revelbayesdelspliceai ↗
PP4 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. Details ▾Hide ▴
Evidence considered
  • No phenotype data reported.
Still missing
  • No clinical phenotype data for variant carriers.
PP5 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. Details ▾Hide ▴
Evidence considered
  • ClinVar: Uncertain significance (VariationID 1481507)
  • No expert panel or multiple-submitter pathogenic classification.
Sources
clinvar ↗
BA1 Allele frequency in gnomAD v4.1 is 0.00025% (4/1,606,858), far below the 1% BA1 threshold. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1 AF=2.49e-6
  • maximum subpopulation AF=3.41e-6 (European non-Finnish).
Sources
gnomad_v4 ↗
BS1 Allele frequency in gnomAD v4.1 is 0.00025% (4/1,606,858), below the 0.3% BS1 threshold for a dominant disorder. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1 AF=0.00025% < 0.3% threshold.
Sources
gnomad_v4 ↗
BS2 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. Details ▾Hide ▴
Evidence considered
  • No confirmed healthy adult observations with phenotype data.
Still missing
  • No phenotype data for the 4 gnomAD allele carriers.
BS3 No well-established functional studies demonstrate no deleterious effect for this variant. Details ▾Hide ▴
Evidence considered
  • No functional studies identified.
Still missing
  • No functional characterization of p.His1927Asp.
BS4 No segregation data available to demonstrate lack of co-segregation with disease. Details ▾Hide ▴
Evidence considered
  • No segregation studies available.
Still missing
  • No family studies.
BP1 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. Details ▾Hide ▴
Evidence considered
  • CACNA1C missense variants are an established disease mechanism (e.g.
  • Timothy syndrome).
Sources
pvs1_gene_context
BP2 No evidence of this variant observed in trans with a pathogenic variant in a dominant disorder. Details ▾Hide ▴
Evidence considered
  • No trans observations reported.
BP5 No evidence of an alternate molecular basis for disease in individuals carrying this variant. Details ▾Hide ▴
Evidence considered
  • No alternate molecular cause identified in any carrier.
Still missing
  • No phenotype or comprehensive genetic workup data for carriers.
BP6 No reputable source classifies this variant as benign. ClinVar classification is Uncertain significance. Details ▾Hide ▴
Evidence considered
  • ClinVar: Uncertain significance (2 submitters).
Sources
clinvar ↗
PS5 No evidence of this variant found in trans with a known pathogenic variant for a recessive disorder. CACNA1C-associated disorders are typically autosomal dominant. Details ▾Hide ▴
Evidence considered
  • No trans observations reported.
Not applicable · 3· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis 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. Details ▾Hide ▴
Evidence considered
  • Variant is a missense substitution in exon 45
  • variant_bucket='other'
  • apply_generic_pvs1_framework=false.
Sources
pvs1_variant_assessment
PM5 N/AUnable to confirm classic same-residue PM5 comparator semantics; no same-residue candidate variants with established pathogenicity were identified. Details ▾Hide ▴
Evidence considered
  • pm5_candidates.json: found=false
  • no same-residue pathogenic comparators.
Sources
pm5_candidates
BP7 N/AThis is a missense variant (p.His1927Asp), not a synonymous or intronic variant outside splice sites. Details ▾Hide ▴
Evidence considered
  • c.5779C>G is a missense substitution.

Identifiers

Gene
CACNA1C
Transcript
NM_000719.7
Coding (HGVS c.)
NM_000719.7:c.5779C>G
Protein (HGVS p.)
NP_000710.5:p.(His1927Asp)
GRCh38
chr12:2686264 C>G
GRCh37
chr12:2795430 C>G
ClinVar
1481507, 1376918

Gene diagram

Every interpreted variant in CACNA1C, mapped onto the exon structure of NM_000719.7. Select a row to find it on the plot.

CACNA1CNM_000719.7
Fetching transcript structure from UCSC…
gnomAD v4.1 4 / 1,606,858 alleles AF 2.49e-06 · 0 homozygotes · FAF 8e-07
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 2.5e-06 · 4 / 1,606,858 alleles · 0 hom · FAF 8e-07
European (non-Finnish)4 / 1,174,716 3.4e-06
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 2.48933e-06; MAF= 0.00025%, 4/1606858 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 3.40508e-06; MAF= 0.00034%, 4/1174716 alleles, homozygotes = 0); grpmax FAF= 8e-07.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat +6 bp
0.000
SpliceAI acceptor gainat +27 bp
0.000
SpliceAI donor lossat +174 bp
0.020
SpliceAI donor gainat -7 bp
0.000
Pangolin splice lossmagnitude shown
-0.030
Pangolin splice gain
0.000

Other predictors

REVEL
0.378
BayesDel
0.079

How the predictions were used

BP4 SupportingMultiple 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). Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta=0.02 (no splicing impact)
  • BayesDel=0.079 (benign range)
  • REVEL=0.378 (intermediate
  • below pathogenic threshold >0.5)
Still missing
  • HCI prior not available for CACNA1C.
Sources
revelbayesdelspliceai ↗
PP3 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). Details ▾Hide ▴
Evidence considered
  • REVEL=0.378 (intermediate
  • below pathogenic threshold)
  • BayesDel=0.079 (benign range)
  • SpliceAI max delta=0.02 (no splice impact)
Sources
revelbayesdelspliceai ↗
BP7 N/AThis is a missense variant (p.His1927Asp), not a synonymous or intronic variant outside splice sites. Details ▾Hide ▴
Evidence considered
  • c.5779C>G is a missense substitution.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.378. BayesDel score = 0.0794366.

3 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.

Recorded publications

  • Long QT Syndrome Overview.
    Adam MP et al. · 1993
    GeneReviews overview of Long QT Syndrome covering clinical presentation, genetic basis, and management. CACNA1C is discussed in the context of Timothy syndrome (LQT8). NM_000719.7:c.5779C>G (p.His1927Asp) was not identified in this review.
    Does not name this variant
    PMID 20301308 ↗
  • Executive summary: HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes.
    Priori SG et al. · 2013
    HRS/EHRA/APHRS expert consensus statement providing clinical guidance for diagnosis and management of inherited primary arrhythmia syndromes (LQTS, Brugada, CPVT). The document discusses gene-level associations including CACNA1C in the context of Timothy syndrome. NM_000719.7:c.5779C>G (p.His1927Asp) was not identified in this consensus document.
    Does not name this variant
    PMID 23994779 ↗
  • ACMG SF v3.1 list for reporting of secondary findings in clinical exome and genome sequencing: A policy statement of the American College of Medical Genetics and Genomics (ACMG).
    Miller DT et al. · 2022
    ACMG SF v3.1 policy statement on secondary findings reporting in clinical exome and genome sequencing, listing genes recommended for opportunistic screening. CACNA1C is not included on the secondary findings gene list. NM_000719.7:c.5779C>G (p.His1927Asp) was not identified in this policy document.
    Does not name this variant
    PMID 35802134 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 4 / 1,606,858 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.020 Open source ↗
ClinVar 2 Uncertain significance Open source ↗
COSMIC Captured COSMIC source record Open source ↗
Cancer hotspots Captured Cancer Hotspots source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 2.48933e-06; MAF= 0.00025%, 4/1606858 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 3.40508e-06; MAF= 0.00034%, 4/1174716 alleles, homozygotes = 0); grpmax FAF= 8e-07.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories). (ClinVarID = 1481507)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.378. BayesDel score = 0.0794366.

Somatic

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.