NM_000719.7:c.5731G>A
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2BS2
The NM_000719.7(CACNA1C):c.5731G>A(p.Gly1911Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000806 in 1,613,618 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar 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 rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CACNA1C | NM_000719.7 | c.5731G>A | p.Gly1911Arg | missense_variant | Exon 45 of 47 | ENST00000399655.6 | NP_000710.5 | |
CACNA1C | NM_001167623.2 | c.5731G>A | p.Gly1911Arg | missense_variant | Exon 45 of 47 | ENST00000399603.6 | NP_001161095.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CACNA1C | ENST00000399603.6 | c.5731G>A | p.Gly1911Arg | missense_variant | Exon 45 of 47 | 5 | NM_001167623.2 | ENSP00000382512.1 | ||
CACNA1C | ENST00000399655.6 | c.5731G>A | p.Gly1911Arg | missense_variant | Exon 45 of 47 | 1 | NM_000719.7 | ENSP00000382563.1 | ||
CACNA1C | ENST00000682544.1 | c.6070G>A | p.Gly2024Arg | missense_variant | Exon 48 of 50 | ENSP00000507184.1 | ||||
CACNA1C | ENST00000406454.8 | c.5944G>A | p.Gly1982Arg | missense_variant | Exon 46 of 48 | 5 | ENSP00000385896.3 | |||
CACNA1C | ENST00000399634.6 | c.5911G>A | p.Gly1971Arg | missense_variant | Exon 45 of 47 | 5 | ENSP00000382542.2 | |||
CACNA1C | ENST00000683824.1 | c.5896G>A | p.Gly1966Arg | missense_variant | Exon 46 of 48 | ENSP00000507867.1 | ||||
CACNA1C | ENST00000347598.9 | c.5875G>A | p.Gly1959Arg | missense_variant | Exon 47 of 49 | 1 | ENSP00000266376.6 | |||
CACNA1C | ENST00000344100.7 | c.5854G>A | p.Gly1952Arg | missense_variant | Exon 45 of 47 | 1 | ENSP00000341092.3 | |||
CACNA1C | ENST00000327702.12 | c.5836G>A | p.Gly1946Arg | missense_variant | Exon 46 of 48 | 1 | ENSP00000329877.7 | |||
CACNA1C | ENST00000399617.6 | c.5836G>A | p.Gly1946Arg | missense_variant | Exon 46 of 48 | 5 | ENSP00000382526.1 | |||
CACNA1C | ENST00000682462.1 | c.5821G>A | p.Gly1941Arg | missense_variant | Exon 45 of 47 | ENSP00000507105.1 | ||||
CACNA1C | ENST00000683781.1 | c.5821G>A | p.Gly1941Arg | missense_variant | Exon 45 of 47 | ENSP00000507434.1 | ||||
CACNA1C | ENST00000683840.1 | c.5821G>A | p.Gly1941Arg | missense_variant | Exon 45 of 47 | ENSP00000507612.1 | ||||
CACNA1C | ENST00000683956.1 | c.5821G>A | p.Gly1941Arg | missense_variant | Exon 45 of 47 | ENSP00000506882.1 | ||||
CACNA1C | ENST00000399638.5 | c.5815G>A | p.Gly1939Arg | missense_variant | Exon 46 of 48 | 1 | ENSP00000382547.1 | |||
CACNA1C | ENST00000335762.10 | c.5806G>A | p.Gly1936Arg | missense_variant | Exon 46 of 48 | 5 | ENSP00000336982.5 | |||
CACNA1C | ENST00000399606.5 | c.5791G>A | p.Gly1931Arg | missense_variant | Exon 46 of 48 | 1 | ENSP00000382515.1 | |||
CACNA1C | ENST00000399621.5 | c.5788G>A | p.Gly1930Arg | missense_variant | Exon 45 of 47 | 1 | ENSP00000382530.1 | |||
CACNA1C | ENST00000399637.5 | c.5788G>A | p.Gly1930Arg | missense_variant | Exon 45 of 47 | 1 | ENSP00000382546.1 | |||
CACNA1C | ENST00000402845.7 | c.5788G>A | p.Gly1930Arg | missense_variant | Exon 45 of 47 | 1 | ENSP00000385724.3 | |||
CACNA1C | ENST00000399629.5 | c.5782G>A | p.Gly1928Arg | missense_variant | Exon 45 of 47 | 1 | ENSP00000382537.1 | |||
CACNA1C | ENST00000682336.1 | c.5773G>A | p.Gly1925Arg | missense_variant | Exon 45 of 47 | ENSP00000507898.1 | ||||
CACNA1C | ENST00000399591.5 | c.5755G>A | p.Gly1919Arg | missense_variant | Exon 44 of 46 | 1 | ENSP00000382500.1 | |||
CACNA1C | ENST00000399595.5 | c.5755G>A | p.Gly1919Arg | missense_variant | Exon 44 of 46 | 1 | ENSP00000382504.1 | |||
CACNA1C | ENST00000399649.5 | c.5749G>A | p.Gly1917Arg | missense_variant | Exon 44 of 46 | 1 | ENSP00000382557.1 | |||
CACNA1C | ENST00000399597.5 | c.5731G>A | p.Gly1911Arg | missense_variant | Exon 45 of 47 | 1 | ENSP00000382506.1 | |||
CACNA1C | ENST00000399601.5 | c.5731G>A | p.Gly1911Arg | missense_variant | Exon 45 of 47 | 1 | ENSP00000382510.1 | |||
CACNA1C | ENST00000399641.6 | c.5731G>A | p.Gly1911Arg | missense_variant | Exon 45 of 47 | 1 | ENSP00000382549.1 | |||
CACNA1C | ENST00000399644.5 | c.5731G>A | p.Gly1911Arg | missense_variant | Exon 45 of 47 | 1 | ENSP00000382552.1 | |||
CACNA1C | ENST00000682835.1 | c.5731G>A | p.Gly1911Arg | missense_variant | Exon 45 of 47 | ENSP00000507282.1 | ||||
CACNA1C | ENST00000683482.1 | c.5722G>A | p.Gly1908Arg | missense_variant | Exon 45 of 47 | ENSP00000507169.1 | ||||
CACNA1C | ENST00000682686.1 | c.5698G>A | p.Gly1900Arg | missense_variant | Exon 44 of 46 | ENSP00000507309.1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152244Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000401 AC: 1AN: 249308Hom.: 0 AF XY: 0.00000739 AC XY: 1AN XY: 135252
GnomAD4 exome AF: 0.00000821 AC: 12AN: 1461374Hom.: 0 Cov.: 32 AF XY: 0.00000825 AC XY: 6AN XY: 726982
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152244Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74380
ClinVar
Submissions by phenotype
Long QT syndrome Uncertain:1
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1911 of the CACNA1C protein (p.Gly1911Arg). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with long QT syndrome or Brugada syndrome (PMID: 25184293, 26230511). This variant is also known as c.5875G>C, p.Gly1959Arg. ClinVar contains an entry for this variant (Variation ID: 842047). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt CACNA1C protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change affects CACNA1C function (PMID: 25184293, 27502440). 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 Uncertain:1
The p.G1911R variant (also known as c.5731G>A), located in coding exon 45 of the CACNA1C gene, results from a G to A substitution at nucleotide position 5731. The glycine at codon 1911 is replaced by arginine, an amino acid with dissimilar properties. This alteration, which is also referenced as c.5875G>C (p.Gly1959Arg), has been reported in an individual suspected to have Timothy syndrome, as well as in a Brugada syndrome cohort and as a secondary cardiac variant in an exome cohort (Ng D et al. Circ Cardiovasc Genet, 2013 Aug;6:337-46; Hennessey JA et al. PLoS One, 2014 Sep;9:e106982; Allegue C et al. PLoS One, 2015 Jul;10:e0133037). Additionally, in vitro studies showed that this alteration may affect protein function (Hennessey JA et al. PLoS One, 2014 Sep;9:e106982; Bai J et al. Sci Rep, 2016 08;6:31262). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at