rs201492706
Variant summary
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.
Frequency
Consequence
NM_000719.7 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Benign. Variant got -12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CACNA1C | NM_000719.7 | c.5150C>G | p.Ala1717Gly | missense_variant | Exon 42 of 47 | ENST00000399655.6 | NP_000710.5 | |
CACNA1C | NM_001167623.2 | c.5150C>G | p.Ala1717Gly | missense_variant | Exon 42 of 47 | ENST00000399603.6 | NP_001161095.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CACNA1C | ENST00000399603.6 | c.5150C>G | p.Ala1717Gly | missense_variant | Exon 42 of 47 | 5 | NM_001167623.2 | ENSP00000382512.1 | ||
CACNA1C | ENST00000399655.6 | c.5150C>G | p.Ala1717Gly | missense_variant | Exon 42 of 47 | 1 | NM_000719.7 | ENSP00000382563.1 | ||
CACNA1C | ENST00000682544.1 | c.5384C>G | p.Ala1795Gly | missense_variant | Exon 44 of 50 | ENSP00000507184.1 | ||||
CACNA1C | ENST00000406454.8 | c.5150C>G | p.Ala1717Gly | missense_variant | Exon 42 of 48 | 5 | ENSP00000385896.3 | |||
CACNA1C | ENST00000399634.6 | c.5117C>G | p.Ala1706Gly | missense_variant | Exon 41 of 47 | 5 | ENSP00000382542.2 | |||
CACNA1C | ENST00000683824.1 | c.5315C>G | p.Ala1772Gly | missense_variant | Exon 43 of 48 | ENSP00000507867.1 | ||||
CACNA1C | ENST00000347598.9 | c.5294C>G | p.Ala1765Gly | missense_variant | Exon 44 of 49 | 1 | ENSP00000266376.6 | |||
CACNA1C | ENST00000344100.7 | c.5273C>G | p.Ala1758Gly | missense_variant | Exon 42 of 47 | 1 | ENSP00000341092.3 | |||
CACNA1C | ENST00000327702.12 | c.5150C>G | p.Ala1717Gly | missense_variant | Exon 42 of 48 | 1 | ENSP00000329877.7 | |||
CACNA1C | ENST00000399617.6 | c.5150C>G | p.Ala1717Gly | missense_variant | Exon 42 of 48 | 5 | ENSP00000382526.1 | |||
CACNA1C | ENST00000682462.1 | c.5240C>G | p.Ala1747Gly | missense_variant | Exon 42 of 47 | ENSP00000507105.1 | ||||
CACNA1C | ENST00000683781.1 | c.5240C>G | p.Ala1747Gly | missense_variant | Exon 42 of 47 | ENSP00000507434.1 | ||||
CACNA1C | ENST00000683840.1 | c.5240C>G | p.Ala1747Gly | missense_variant | Exon 42 of 47 | ENSP00000507612.1 | ||||
CACNA1C | ENST00000683956.1 | c.5240C>G | p.Ala1747Gly | missense_variant | Exon 42 of 47 | ENSP00000506882.1 | ||||
CACNA1C | ENST00000399638.5 | c.5234C>G | p.Ala1745Gly | missense_variant | Exon 43 of 48 | 1 | ENSP00000382547.1 | |||
CACNA1C | ENST00000335762.10 | c.5225C>G | p.Ala1742Gly | missense_variant | Exon 43 of 48 | 5 | ENSP00000336982.5 | |||
CACNA1C | ENST00000399606.5 | c.5210C>G | p.Ala1737Gly | missense_variant | Exon 43 of 48 | 1 | ENSP00000382515.1 | |||
CACNA1C | ENST00000399621.5 | c.5207C>G | p.Ala1736Gly | missense_variant | Exon 42 of 47 | 1 | ENSP00000382530.1 | |||
CACNA1C | ENST00000399637.5 | c.5207C>G | p.Ala1736Gly | missense_variant | Exon 42 of 47 | 1 | ENSP00000382546.1 | |||
CACNA1C | ENST00000402845.7 | c.5207C>G | p.Ala1736Gly | missense_variant | Exon 42 of 47 | 1 | ENSP00000385724.3 | |||
CACNA1C | ENST00000399629.5 | c.5201C>G | p.Ala1734Gly | missense_variant | Exon 42 of 47 | 1 | ENSP00000382537.1 | |||
CACNA1C | ENST00000682336.1 | c.5192C>G | p.Ala1731Gly | missense_variant | Exon 42 of 47 | ENSP00000507898.1 | ||||
CACNA1C | ENST00000399591.5 | c.5174C>G | p.Ala1725Gly | missense_variant | Exon 41 of 46 | 1 | ENSP00000382500.1 | |||
CACNA1C | ENST00000399595.5 | c.5174C>G | p.Ala1725Gly | missense_variant | Exon 41 of 46 | 1 | ENSP00000382504.1 | |||
CACNA1C | ENST00000399649.5 | c.5168C>G | p.Ala1723Gly | missense_variant | Exon 41 of 46 | 1 | ENSP00000382557.1 | |||
CACNA1C | ENST00000399597.5 | c.5150C>G | p.Ala1717Gly | missense_variant | Exon 42 of 47 | 1 | ENSP00000382506.1 | |||
CACNA1C | ENST00000399601.5 | c.5150C>G | p.Ala1717Gly | missense_variant | Exon 42 of 47 | 1 | ENSP00000382510.1 | |||
CACNA1C | ENST00000399641.6 | c.5150C>G | p.Ala1717Gly | missense_variant | Exon 42 of 47 | 1 | ENSP00000382549.1 | |||
CACNA1C | ENST00000399644.5 | c.5150C>G | p.Ala1717Gly | missense_variant | Exon 42 of 47 | 1 | ENSP00000382552.1 | |||
CACNA1C | ENST00000682835.1 | c.5150C>G | p.Ala1717Gly | missense_variant | Exon 42 of 47 | ENSP00000507282.1 | ||||
CACNA1C | ENST00000683482.1 | c.5141C>G | p.Ala1714Gly | missense_variant | Exon 42 of 47 | ENSP00000507169.1 | ||||
CACNA1C | ENST00000682686.1 | c.5117C>G | p.Ala1706Gly | missense_variant | Exon 41 of 46 | ENSP00000507309.1 |
Frequencies
GnomAD3 genomes AF: 0.000499 AC: 76AN: 152196Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000846 AC: 206AN: 243628Hom.: 1 AF XY: 0.000921 AC XY: 122AN XY: 132502
GnomAD4 exome AF: 0.000597 AC: 870AN: 1456958Hom.: 5 Cov.: 31 AF XY: 0.000641 AC XY: 464AN XY: 724114
GnomAD4 genome AF: 0.000499 AC: 76AN: 152314Hom.: 0 Cov.: 33 AF XY: 0.000430 AC XY: 32AN XY: 74478
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:3
- -
This variant is associated with the following publications: (PMID: 22840528, 20817017) -
CACNA1C: BS1, BS2 -
- -
Long QT syndrome Uncertain:1Benign:1
Criteria: BS1, PP2 -
- -
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
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. -
Restrictive cardiomyopathy;C0023976:Long QT syndrome Uncertain:1
- -
not specified Benign:1
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
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
Found in patient having exome sequencing for an unrelated indication. No known history of Brugada syndrome. -
Cardiovascular phenotype Benign:1
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