rs374528680

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

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

CACNA1C
NM_000719.7 missense

Scores

2
4
10

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 5.10
Variant links:
Genes affected
CACNA1C (HGNC:1390): (calcium voltage-gated channel subunit alpha1 C) This gene encodes an alpha-1 subunit of a voltage-dependent calcium channel. Calcium channels mediate the influx of calcium ions into the cell upon membrane polarization. The alpha-1 subunit consists of 24 transmembrane segments and forms the pore through which ions pass into the cell. The calcium channel consists of a complex of alpha-1, alpha-2/delta, beta, and gamma subunits in a 1:1:1:1 ratio. There are multiple isoforms of each of these proteins, either encoded by different genes or the result of alternative splicing of transcripts. The protein encoded by this gene binds to and is inhibited by dihydropyridine. Alternative splicing results in many transcript variants encoding different proteins. Some of the predicted proteins may not produce functional ion channel subunits. [provided by RefSeq, Oct 2012]
CACNA1C-AS1 (HGNC:40119): (CACNA1C antisense RNA 1)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PP2
Missense variant in the CACNA1C gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 45 curated pathogenic missense variants (we use a threshold of 10). The gene has 91 curated benign missense variants. Gene score misZ: 6.4654 (above the threshold of 3.09). Trascript score misZ: 7.2674 (above the threshold of 3.09). GenCC associations: The gene is linked to intellectual disability, neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizures, Brugada syndrome, long QT syndrome, short QT syndrome, long qt syndrome 8, Timothy syndrome, Brugada syndrome 3.
BS2
High AC in GnomAdExome4 at 12 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CACNA1CNM_000719.7 linkc.5731G>A p.Gly1911Arg missense_variant Exon 45 of 47 ENST00000399655.6 NP_000710.5 Q13936-12
CACNA1CNM_001167623.2 linkc.5731G>A p.Gly1911Arg missense_variant Exon 45 of 47 ENST00000399603.6 NP_001161095.1 Q13936-37

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CACNA1CENST00000399603.6 linkc.5731G>A p.Gly1911Arg missense_variant Exon 45 of 47 5 NM_001167623.2 ENSP00000382512.1 Q13936-37
CACNA1CENST00000399655.6 linkc.5731G>A p.Gly1911Arg missense_variant Exon 45 of 47 1 NM_000719.7 ENSP00000382563.1 Q13936-12
CACNA1CENST00000682544.1 linkc.6070G>A p.Gly2024Arg missense_variant Exon 48 of 50 ENSP00000507184.1 A0A804HIR0
CACNA1CENST00000406454.8 linkc.5944G>A p.Gly1982Arg missense_variant Exon 46 of 48 5 ENSP00000385896.3 F5GY28
CACNA1CENST00000399634.6 linkc.5911G>A p.Gly1971Arg missense_variant Exon 45 of 47 5 ENSP00000382542.2 E9PDI6
CACNA1CENST00000683824.1 linkc.5896G>A p.Gly1966Arg missense_variant Exon 46 of 48 ENSP00000507867.1 A0A804HKC4
CACNA1CENST00000347598.9 linkc.5875G>A p.Gly1959Arg missense_variant Exon 47 of 49 1 ENSP00000266376.6 Q13936-11
CACNA1CENST00000344100.7 linkc.5854G>A p.Gly1952Arg missense_variant Exon 45 of 47 1 ENSP00000341092.3 Q13936-14
CACNA1CENST00000327702.12 linkc.5836G>A p.Gly1946Arg missense_variant Exon 46 of 48 1 ENSP00000329877.7 A0A0A0MR67
CACNA1CENST00000399617.6 linkc.5836G>A p.Gly1946Arg missense_variant Exon 46 of 48 5 ENSP00000382526.1 A0A0A0MSA1
CACNA1CENST00000682462.1 linkc.5821G>A p.Gly1941Arg missense_variant Exon 45 of 47 ENSP00000507105.1 A0A804HIJ8
CACNA1CENST00000683781.1 linkc.5821G>A p.Gly1941Arg missense_variant Exon 45 of 47 ENSP00000507434.1 A0A804HJB6
CACNA1CENST00000683840.1 linkc.5821G>A p.Gly1941Arg missense_variant Exon 45 of 47 ENSP00000507612.1 A0A804HJR1
CACNA1CENST00000683956.1 linkc.5821G>A p.Gly1941Arg missense_variant Exon 45 of 47 ENSP00000506882.1 A0A804HI37
CACNA1CENST00000399638.5 linkc.5815G>A p.Gly1939Arg missense_variant Exon 46 of 48 1 ENSP00000382547.1 Q13936-31
CACNA1CENST00000335762.10 linkc.5806G>A p.Gly1936Arg missense_variant Exon 46 of 48 5 ENSP00000336982.5 F5H522
CACNA1CENST00000399606.5 linkc.5791G>A p.Gly1931Arg missense_variant Exon 46 of 48 1 ENSP00000382515.1 Q13936-30
CACNA1CENST00000399621.5 linkc.5788G>A p.Gly1930Arg missense_variant Exon 45 of 47 1 ENSP00000382530.1 Q13936-24
CACNA1CENST00000399637.5 linkc.5788G>A p.Gly1930Arg missense_variant Exon 45 of 47 1 ENSP00000382546.1 Q13936-27
CACNA1CENST00000402845.7 linkc.5788G>A p.Gly1930Arg missense_variant Exon 45 of 47 1 ENSP00000385724.3 Q13936-13
CACNA1CENST00000399629.5 linkc.5782G>A p.Gly1928Arg missense_variant Exon 45 of 47 1 ENSP00000382537.1 Q13936-32
CACNA1CENST00000682336.1 linkc.5773G>A p.Gly1925Arg missense_variant Exon 45 of 47 ENSP00000507898.1 A0A804HKE9
CACNA1CENST00000399591.5 linkc.5755G>A p.Gly1919Arg missense_variant Exon 44 of 46 1 ENSP00000382500.1 Q13936-29
CACNA1CENST00000399595.5 linkc.5755G>A p.Gly1919Arg missense_variant Exon 44 of 46 1 ENSP00000382504.1 Q13936-25
CACNA1CENST00000399649.5 linkc.5749G>A p.Gly1917Arg missense_variant Exon 44 of 46 1 ENSP00000382557.1 Q13936-15
CACNA1CENST00000399597.5 linkc.5731G>A p.Gly1911Arg missense_variant Exon 45 of 47 1 ENSP00000382506.1 Q13936-22
CACNA1CENST00000399601.5 linkc.5731G>A p.Gly1911Arg missense_variant Exon 45 of 47 1 ENSP00000382510.1 Q13936-20
CACNA1CENST00000399641.6 linkc.5731G>A p.Gly1911Arg missense_variant Exon 45 of 47 1 ENSP00000382549.1 Q13936-23
CACNA1CENST00000399644.5 linkc.5731G>A p.Gly1911Arg missense_variant Exon 45 of 47 1 ENSP00000382552.1 Q13936-21
CACNA1CENST00000682835.1 linkc.5731G>A p.Gly1911Arg missense_variant Exon 45 of 47 ENSP00000507282.1 A0A804HIZ0
CACNA1CENST00000683482.1 linkc.5722G>A p.Gly1908Arg missense_variant Exon 45 of 47 ENSP00000507169.1 Q13936-35
CACNA1CENST00000682686.1 linkc.5698G>A p.Gly1900Arg missense_variant Exon 44 of 46 ENSP00000507309.1 Q13936-19

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152244
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000401
AC:
1
AN:
249308
Hom.:
0
AF XY:
0.00000739
AC XY:
1
AN XY:
135252
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000885
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000821
AC:
12
AN:
1461374
Hom.:
0
Cov.:
32
AF XY:
0.00000825
AC XY:
6
AN XY:
726982
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000989
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152244
Hom.:
0
Cov.:
33
AF XY:
0.0000134
AC XY:
1
AN XY:
74380
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000756

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Long QT syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 29, 2025This 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
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsNov 27, 2021The 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
-0.17
T
BayesDel_noAF
Benign
-0.48
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Benign
0.018
T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.;T
Eigen
Benign
0.14
Eigen_PC
Benign
0.19
FATHMM_MKL
Uncertain
0.94
D
M_CAP
Pathogenic
0.41
D
MetaRNN
Uncertain
0.61
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Benign
-0.85
T
PrimateAI
Uncertain
0.49
T
PROVEAN
Benign
-1.0
N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;.
REVEL
Pathogenic
0.68
Sift
Benign
0.088
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;.
Sift4G
Benign
0.40
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen
0.0030, 0.40, 0.25, 0.81, 0.77, 0.90, 0.015, 0.0010, 0.92, 0.57, 0.95, 0.0
.;B;B;B;P;P;P;P;B;B;P;P;P;P;P;.;P;P;.;.;.;B;.
Vest4
0.60
MVP
0.42
MPC
0.31
ClinPred
0.71
D
GERP RS
4.8
gMVP
0.45

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs374528680; hg19: chr12-2795382; API