rs763738559
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2BS2
The NM_000719.7(CACNA1C):c.1753G>A(p.Val585Met) variant causes a missense change. The variant allele was found at a frequency of 0.000062 in 1,613,040 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. V585A) has been classified as Uncertain significance.
Frequency
Consequence
NM_000719.7 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CACNA1C | NM_000719.7 | c.1753G>A | p.Val585Met | missense_variant | 13/47 | ENST00000399655.6 | |
CACNA1C | NM_001167623.2 | c.1753G>A | p.Val585Met | missense_variant | 13/47 | ENST00000399603.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CACNA1C | ENST00000399603.6 | c.1753G>A | p.Val585Met | missense_variant | 13/47 | 5 | NM_001167623.2 | ||
CACNA1C | ENST00000399655.6 | c.1753G>A | p.Val585Met | missense_variant | 13/47 | 1 | NM_000719.7 |
Frequencies
GnomAD3 genomes ? AF: 0.0000723 AC: 11AN: 152148Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000323 AC: 8AN: 247354Hom.: 0 AF XY: 0.00000746 AC XY: 1AN XY: 134076
GnomAD4 exome AF: 0.0000609 AC: 89AN: 1460892Hom.: 0 Cov.: 31 AF XY: 0.0000537 AC XY: 39AN XY: 726608
GnomAD4 genome ? AF: 0.0000723 AC: 11AN: 152148Hom.: 0 Cov.: 32 AF XY: 0.0000942 AC XY: 7AN XY: 74324
ClinVar
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 30, 2020 | Has been reported in an individual with sudden unexplained death at 36 years of age, and cardiac findings on autopsy showed interstitial fibrosis and myocyte hypertrophy (Shanks et al., 2018); however, a frameshift variant in the A-band of the TTN gene was also identified and no family history or segregation details were reported.; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29915097) - |
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Timothy syndrome;C2678478:Brugada syndrome 3;CN260585:Long qt syndrome 8 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Aug 18, 2021 | - - |
Long QT syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 01, 2022 | This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 585 of the CACNA1C protein (p.Val585Met). This variant is present in population databases (rs763738559, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with CACNA1C-related conditions. ClinVar contains an entry for this variant (Variation ID: 519274). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CACNA1C protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 07, 2022 | 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at