rs369255950
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2BS2
The NM_000719.7(CACNA1C):c.1487G>A(p.Arg496Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000273 in 1,612,530 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. R496W) has been classified as Likely benign.
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.1487G>A | p.Arg496Gln | missense_variant | 11/47 | ENST00000399655.6 | |
CACNA1C | NM_001167623.2 | c.1487G>A | p.Arg496Gln | missense_variant | 11/47 | ENST00000399603.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CACNA1C | ENST00000399603.6 | c.1487G>A | p.Arg496Gln | missense_variant | 11/47 | 5 | NM_001167623.2 | ||
CACNA1C | ENST00000399655.6 | c.1487G>A | p.Arg496Gln | missense_variant | 11/47 | 1 | NM_000719.7 |
Frequencies
GnomAD3 genomes ? AF: 0.0000395 AC: 6AN: 152024Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000441 AC: 11AN: 249244Hom.: 0 AF XY: 0.0000592 AC XY: 8AN XY: 135218
GnomAD4 exome AF: 0.0000260 AC: 38AN: 1460506Hom.: 0 Cov.: 30 AF XY: 0.0000358 AC XY: 26AN XY: 726644
GnomAD4 genome ? AF: 0.0000395 AC: 6AN: 152024Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74240
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Mar 03, 2017 | The R496Q variant of uncertain significance in the CACNA1C gene has not been published as pathogenic or benign to our knowledge. This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). In addition, R496Q is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution also occurs at a position that is conserved across species. Furthermore, the majority of in silico algorithms predict R496Q is probably damaging to the protein structure/function. Therefore, additional evidence is needed to determine whether this variant is pathogenic or benign. - |
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 03, 2021 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Dec 01, 2023 | - - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 20, 2021 | The p.R496Q variant (also known as c.1487G>A), located in coding exon 11 of the CACNA1C gene, results from a G to A substitution at nucleotide position 1487. The arginine at codon 496 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Long QT syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 11, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at