chr12-2686216-G-C
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 1P and 10B. PP2BP4BP6BS1BS2
The NM_000719.7(CACNA1C):āc.5731G>Cā(p.Gly1911Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000477 in 1,613,618 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000719.7 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
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CACNA1C | NM_000719.7 | c.5731G>C | p.Gly1911Arg | missense_variant | Exon 45 of 47 | ENST00000399655.6 | NP_000710.5 | |
CACNA1C | NM_001167623.2 | c.5731G>C | 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>C | p.Gly1911Arg | missense_variant | Exon 45 of 47 | 5 | NM_001167623.2 | ENSP00000382512.1 | ||
CACNA1C | ENST00000399655.6 | c.5731G>C | p.Gly1911Arg | missense_variant | Exon 45 of 47 | 1 | NM_000719.7 | ENSP00000382563.1 | ||
CACNA1C | ENST00000682544.1 | c.6070G>C | p.Gly2024Arg | missense_variant | Exon 48 of 50 | ENSP00000507184.1 | ||||
CACNA1C | ENST00000406454.8 | c.5944G>C | p.Gly1982Arg | missense_variant | Exon 46 of 48 | 5 | ENSP00000385896.3 | |||
CACNA1C | ENST00000399634.6 | c.5911G>C | p.Gly1971Arg | missense_variant | Exon 45 of 47 | 5 | ENSP00000382542.2 | |||
CACNA1C | ENST00000683824.1 | c.5896G>C | p.Gly1966Arg | missense_variant | Exon 46 of 48 | ENSP00000507867.1 | ||||
CACNA1C | ENST00000347598.9 | c.5875G>C | p.Gly1959Arg | missense_variant | Exon 47 of 49 | 1 | ENSP00000266376.6 | |||
CACNA1C | ENST00000344100.7 | c.5854G>C | p.Gly1952Arg | missense_variant | Exon 45 of 47 | 1 | ENSP00000341092.3 | |||
CACNA1C | ENST00000327702.12 | c.5836G>C | p.Gly1946Arg | missense_variant | Exon 46 of 48 | 1 | ENSP00000329877.7 | |||
CACNA1C | ENST00000399617.6 | c.5836G>C | p.Gly1946Arg | missense_variant | Exon 46 of 48 | 5 | ENSP00000382526.1 | |||
CACNA1C | ENST00000682462.1 | c.5821G>C | p.Gly1941Arg | missense_variant | Exon 45 of 47 | ENSP00000507105.1 | ||||
CACNA1C | ENST00000683781.1 | c.5821G>C | p.Gly1941Arg | missense_variant | Exon 45 of 47 | ENSP00000507434.1 | ||||
CACNA1C | ENST00000683840.1 | c.5821G>C | p.Gly1941Arg | missense_variant | Exon 45 of 47 | ENSP00000507612.1 | ||||
CACNA1C | ENST00000683956.1 | c.5821G>C | p.Gly1941Arg | missense_variant | Exon 45 of 47 | ENSP00000506882.1 | ||||
CACNA1C | ENST00000399638.5 | c.5815G>C | p.Gly1939Arg | missense_variant | Exon 46 of 48 | 1 | ENSP00000382547.1 | |||
CACNA1C | ENST00000335762.10 | c.5806G>C | p.Gly1936Arg | missense_variant | Exon 46 of 48 | 5 | ENSP00000336982.5 | |||
CACNA1C | ENST00000399606.5 | c.5791G>C | p.Gly1931Arg | missense_variant | Exon 46 of 48 | 1 | ENSP00000382515.1 | |||
CACNA1C | ENST00000399621.5 | c.5788G>C | p.Gly1930Arg | missense_variant | Exon 45 of 47 | 1 | ENSP00000382530.1 | |||
CACNA1C | ENST00000399637.5 | c.5788G>C | p.Gly1930Arg | missense_variant | Exon 45 of 47 | 1 | ENSP00000382546.1 | |||
CACNA1C | ENST00000402845.7 | c.5788G>C | p.Gly1930Arg | missense_variant | Exon 45 of 47 | 1 | ENSP00000385724.3 | |||
CACNA1C | ENST00000399629.5 | c.5782G>C | p.Gly1928Arg | missense_variant | Exon 45 of 47 | 1 | ENSP00000382537.1 | |||
CACNA1C | ENST00000682336.1 | c.5773G>C | p.Gly1925Arg | missense_variant | Exon 45 of 47 | ENSP00000507898.1 | ||||
CACNA1C | ENST00000399591.5 | c.5755G>C | p.Gly1919Arg | missense_variant | Exon 44 of 46 | 1 | ENSP00000382500.1 | |||
CACNA1C | ENST00000399595.5 | c.5755G>C | p.Gly1919Arg | missense_variant | Exon 44 of 46 | 1 | ENSP00000382504.1 | |||
CACNA1C | ENST00000399649.5 | c.5749G>C | p.Gly1917Arg | missense_variant | Exon 44 of 46 | 1 | ENSP00000382557.1 | |||
CACNA1C | ENST00000399597.5 | c.5731G>C | p.Gly1911Arg | missense_variant | Exon 45 of 47 | 1 | ENSP00000382506.1 | |||
CACNA1C | ENST00000399601.5 | c.5731G>C | p.Gly1911Arg | missense_variant | Exon 45 of 47 | 1 | ENSP00000382510.1 | |||
CACNA1C | ENST00000399641.6 | c.5731G>C | p.Gly1911Arg | missense_variant | Exon 45 of 47 | 1 | ENSP00000382549.1 | |||
CACNA1C | ENST00000399644.5 | c.5731G>C | p.Gly1911Arg | missense_variant | Exon 45 of 47 | 1 | ENSP00000382552.1 | |||
CACNA1C | ENST00000682835.1 | c.5731G>C | p.Gly1911Arg | missense_variant | Exon 45 of 47 | ENSP00000507282.1 | ||||
CACNA1C | ENST00000683482.1 | c.5722G>C | p.Gly1908Arg | missense_variant | Exon 45 of 47 | ENSP00000507169.1 | ||||
CACNA1C | ENST00000682686.1 | c.5698G>C | p.Gly1900Arg | missense_variant | Exon 44 of 46 | ENSP00000507309.1 |
Frequencies
GnomAD3 genomes AF: 0.0000460 AC: 7AN: 152244Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000602 AC: 15AN: 249308Hom.: 1 AF XY: 0.0000591 AC XY: 8AN XY: 135252
GnomAD4 exome AF: 0.0000479 AC: 70AN: 1461374Hom.: 1 Cov.: 32 AF XY: 0.0000316 AC XY: 23AN XY: 726982
GnomAD4 genome AF: 0.0000460 AC: 7AN: 152244Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74380
ClinVar
Submissions by phenotype
not provided Uncertain:3
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Timothy syndrome Uncertain:2
This sequence change in CACNA1C is predicted to replace glycine with arginine at codon 1911, p.(Gly1911Arg). The glycine residue is moderately conserved (100 vertebrates, UCSC), and is located in the cytoplasmic region. There is a large physicochemical difference between glycine and arginine. The highest population minor allele frequency in the population database gnomAD v2.1 is 0.03% (11/19,536 alleles) in the East Asian population. This variant has been reported in multiple probands with cardiac phenotypes (PMID: 25184293, 26230511, 23861362). An in vitro functional study using Cav1.2 channel vectors expressed in HEK293T cells showed increased calcium ion production during cardiac action potential suggesting that this variant impacts protein function however limited controls were included in the assay (PMID: 25184293). Computational evidence is uninformative for the missense substitution (REVEL = 0.629). Based on the classification scheme RMH Modified ACMG Guidelines v1.6.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: none. -
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not specified Uncertain:1
Variant summary: CACNA1C c.5731G>C (p.Gly1911Arg) results in a non-conservative amino acid change located in the Voltage-gated calcium channel subunit alpha, C-terminal domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6e-05 in 249708 control chromosomes, predominantly at a frequency of 0.00056 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 56 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 a benign polymorphism found primarily in populations of East Asian origin. The variant, c.5731G>C, has been reported in the literature in individuals affected with Brugada Syndrome, long QT syndrome or sudden unexplained infant death (Allegue_2015, Hennessey_2014). However, one publication, Hennessey_2014, suggests the variant is inherited from the asymptomatic father, although his DNA was not available for analysis. In electrophysiological analyses, the variant was observed to cause a gain of function of CaV1.2 suggesting increased susceptibility for arrhythmias in certain clinical settings (Hennessey_2014). Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS - possibly benign. -
Cardiomyopathy Uncertain:1
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Timothy syndrome;C2678478:Brugada syndrome 3;CN260585:Long qt syndrome 8 Uncertain:1
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Long QT syndrome Benign:1
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Cardiovascular phenotype Benign:1
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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at