Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2
The NM_000719.7(CACNA1C):c.1468G>A(p.Gly490Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000399 in 1,605,038 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G490G) has been classified as Likely benign.
CACNA1C (HGNC:1390): (calcium voltage-gated channel subunit alpha1 C) This gene encodes an alpha-1 subunit of a voltage-dependent calcium channel. Calcium channels mediate the influx of calcium ions into the cell upon membrane polarization. The alpha-1 subunit consists of 24 transmembrane segments and forms the pore through which ions pass into the cell. The calcium channel consists of a complex of alpha-1, alpha-2/delta, beta, and gamma subunits in a 1:1:1:1 ratio. There are multiple isoforms of each of these proteins, either encoded by different genes or the result of alternative splicing of transcripts. The protein encoded by this gene binds to and is inhibited by dihydropyridine. Alternative splicing results in many transcript variants encoding different proteins. Some of the predicted proteins may not produce functional ion channel subunits. [provided by RefSeq, Oct 2012]
PP2 - Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease
Missense variant where missense usually causes diseases, CACNA1C
BP4
?
BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (MetaRNN=0.014768004).
BP6
?
BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 12-2550020-G-A is Benign according to our data. Variant chr12-2550020-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 17634.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=2, Benign=3, not_provided=2}.
BS1
?
BS1 - Allele frequency is greater than expected for disorder
Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000403 (585/1452762) while in subpopulation MID AF= 0.00174 (10/5756). AF 95% confidence interval is 0.000942. There are 3 homozygotes in gnomad4_exome. There are 296 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck.
BS2
?
BS2 - Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age
Uncertain significance, no assertion criteria provided
clinical testing
Clinical Genetics, Academic Medical Center
-
- -
Likely benign, criteria provided, single submitter
clinical testing
GeneDx
Jun 17, 2021
Published functional studies demonstrate no damaging effect (Antzelevitch et al., 2007).; This variant is associated with the following publications: (PMID: 22581653, 17224476, 20301690, 20817017, 23414114, 24183960, 25333069, 26707467, 27711072, 25974115, 30027834, 30847666, 26582918, 28807990, 30821013, 27535533) -
Uncertain significance, no assertion criteria provided
clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
-
- -
Uncertain significance, criteria provided, single submitter
clinical testing
Eurofins Ntd Llc (ga)
Aug 26, 2015
- -
Brugada syndrome 3 Pathogenic:1Other:1
Pathogenic, no assertion criteria provided
literature only
OMIM
Jan 30, 2007
- -
not provided, no classification provided
literature only
GeneReviews
-
- -
not specified Benign:2
Benign, criteria provided, single submitter
clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Likely benign, criteria provided, single submitter
clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Oct 12, 2023
Variant summary: CACNA1C c.1468G>A (p.Gly490Arg) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00067 in 231558 control chromosomes (gnomAD). The observed variant frequency is approximately 67 fold of the estimated maximal expected allele frequency for a pathogenic variant in CACNA1C causing Arrhythmia phenotype (1e-05), strongly suggesting that the variant is benign. This variant has been reported in individuals affected with Brugada syndrome, hypertrophic cardiomyopathy, and early repolarization syndrome, without strong evidence for causality (examples: Antzelevitch_2007, D'Argenio_2014, Chen_2021). Published functional studies demonstrate no damaging effect from this variant (Antzelevitch et al., 2007). The following publications have been ascertained in the context of this evaluation (PMID: 17224476, 24183960, 34222376). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as benign/likely benign (n=2) and VUS (n=2). Based on the evidence outlined above, the variant was classified as likely benign. -
Long QT syndrome 1 Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute
Mar 02, 2020
- -
CACNA1C-related disorder Benign:1
Likely benign, criteria provided, single submitter
clinical testing
PreventionGenetics, part of Exact Sciences
Feb 28, 2024
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Timothy syndrome Benign:1
Benign, criteria provided, single submitter
clinical testing
Mendelics
Aug 22, 2023
- -
Long QT syndrome Benign:1
Likely benign, criteria provided, single submitter
clinical testing
Invitae
Jan 27, 2024
- -
Cardiovascular phenotype Benign:1
Benign, criteria provided, single submitter
clinical testing
Ambry Genetics
Sep 06, 2017
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Brugada syndrome Other:1
not provided, no classification provided
literature only
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust
-
This variant has been reported as associated with Brugada syndrome in the following publications (PMID:17224476;PMID:20817017). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. -
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