Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2
The NM_000719.7(CACNA1C):c.5150C>G(p.Ala1717Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000588 in 1,609,272 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1717T) 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=0.0071842372).
BP6
?
BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 12-2679502-C-G is Benign according to our data. Variant chr12-2679502-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 93411.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=3, Benign=2}. Variant chr12-2679502-C-G is described in Lovd as [Likely_benign].
BS1
?
BS1 - Allele frequency is greater than expected for disorder
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000499 (76/152314) while in subpopulation AMR AF= 0.00098 (15/15302). AF 95% confidence interval is 0.000604. There are 0 homozygotes in gnomad4. There are 32 alleles in male gnomad4 subpopulation. 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
This variant is associated with the following publications: (PMID: 22840528, 20817017) -
Benign, criteria provided, single submitter
clinical testing
CeGaT Center for Human Genetics Tuebingen
Sep 01, 2023
CACNA1C: BS1, BS2 -
Uncertain significance, criteria provided, single submitter
clinical testing
Eurofins Ntd Llc (ga)
Feb 06, 2015
- -
Likely benign, criteria provided, single submitter
research
Biesecker Lab/Clinical Genomics Section, National Institutes of Health
Jun 24, 2013
- -
Long QT syndrome Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter
research
Dept of Medical Biology, Uskudar University
Jan 08, 2024
Criteria: BS1, PP2 -
Likely benign, criteria provided, single submitter
clinical testing
Invitae
Jan 29, 2024
- -
Timothy syndrome;C2678478:Brugada syndrome 3;C5774213:Neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizures;CN260585:Long qt syndrome 8 Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago
Mar 30, 2021
CACNA1C NM_000719.6 exon 42 p.Ala1717Gly (c.5150C>G): This variant has not been reported in the literature but is present in 0.1% (41/34056) of Latino alleles, including 1 homozygote, in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs201492706). This variant is present in ClinVar, with several labs classifying this variant as Likely Benign (Variation ID:93411). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant suggests that this variant does not cause disease, but requires further evidence. Therefore this variant is classified as Likely Benign. -
Uncertain significance, no assertion criteria provided
clinical testing
Blueprint Genetics
Jun 24, 2014
- -
not specified Benign:1
Likely benign, criteria provided, single submitter
clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Mar 18, 2019
Variant summary: CACNA1C c.5150C>G (p.Ala1717Gly) results in a non-conservative amino acid change located in the Voltage-gated calcium channel subunit alpha, C-terminal of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00076 in 272838 control chromosomes in the gnomAD database, including 1 homozygotes. The observed variant frequency is approximately 75.87 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. c.5150C>G has been reported in the literature in individuals affected with cardiac phenotypes (Burashnikov_2010, Crotti_2012, Forleo_2017, Kostareva_2016, Wemhoner_2015) however without strong evidence for causality. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as likely benign. -
CACNA1C-related disorder Benign:1
Likely benign, criteria provided, single submitter
clinical testing
PreventionGenetics, part of Exact Sciences
Feb 16, 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). -
Brugada syndrome Benign:1
Likely benign, no assertion criteria provided
research
CSER _CC_NCGL, University of Washington
Aug 01, 2016
Found in patient having exome sequencing for an unrelated indication. No known history of Brugada syndrome. -
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter
clinical testing
Ambry Genetics
Jun 28, 2018
This alteration is classified as likely 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. -