rs773211348

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP2

The NM_000719.7(CACNA1C):c.70C>T(p.Arg24Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000152 in 1,578,244 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R24H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

CACNA1C
NM_000719.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 3.65

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PP2

Missense variant where missense usually causes diseases, CACNA1C

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1C	NM_000719.7 linkuse as main transcript	c.70C>T	p.Arg24Cys	missense_variant	2/47	ENST00000399655.6
CACNA1C	NM_001167623.2 linkuse as main transcript	c.70C>T	p.Arg24Cys	missense_variant	2/47	ENST00000399603.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1C	ENST00000399603.6 linkuse as main transcript	c.70C>T	p.Arg24Cys	missense_variant	2/47	5	NM_001167623.2		Q13936-37
CACNA1C	ENST00000399655.6 linkuse as main transcript	c.70C>T	p.Arg24Cys	missense_variant	2/47	1	NM_000719.7		Q13936-12

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152272

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000147

AC:

AN:

1425972

Hom.:

Cov.:

AF XY:

0.0000184

AC XY:

AN XY:

704752

show subpopulations

Gnomad4 AFR exome

AF:

0.0000307

Gnomad4 AMR exome

AF:

0.0000240

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000371

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000146

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152272

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74394

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000264

ExAC

AF:

0.00000830

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Dec 31, 2012

p.Arg24Cys (CGC>TGC): c.70 C>T in exon 2 of the CACNA1C gene (NM_000719.6). The Arg24Cys variant in the CACNA1C gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Arg24Cys results in a non-conservative amino acid substitution of a positively charged Arginine with a neutral, polar Cysteine at a position that is conserved across species. In silico analysis predicts Arg24Cys is possibly damaging to the protein structure/function. The NHLBI ESP Exome Variant Server reports Arg24Cys was not observed in approximately 6,000 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. Nevertheless, no mutations in nearby codons have been reported in association with LQTS. With the clinical and molecular information available at this time, we cannot definitively determine if Arg24Cys is a disease-causing mutation or a rare benign variant. The variant is found in LQT panel(s). -

Long QT syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 09, 2024

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 24 of the CACNA1C protein (p.Arg24Cys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with long QT Syndrome (PMID: 31737537). ClinVar contains an entry for this variant (Variation ID: 190675). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CACNA1C protein function with a negative predictive value of 95%. 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 submitter

clinical testing

Ambry Genetics

Sep 20, 2021

The p.R24C variant (also known as c.70C>T), located in coding exon 2 of the CACNA1C gene, results from a C to T substitution at nucleotide position 70. The arginine at codon 24 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in a Brugada syndrome cohort; however, clinical details were limited (Marschall C et al. Cardiovasc Diagn Ther, 2019 Oct;9:S292-S298). This missense alteration is located in a region that has a low rate of benign missense variation (Lek M et al. Nature. 2016 Aug 18;536(7616):285-91; DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources. Firth H.V. et al. 2009. Am.J.Hum.Genet. 84, 524-533 (DOI: dx.doi.org/10/1016/j.ajhg.2009.03.010)). This amino acid position is well 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

CardioboostArm

Benign

0.00020

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Uncertain

0.020

Cadd

Pathogenic

Dann

Pathogenic

1.0

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Uncertain

0.89

M_CAP

Benign

0.064

MetaRNN

Uncertain

0.50

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Pathogenic

0.91

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

PrimateAI

Uncertain

0.77

PROVEAN

Pathogenic

-5.7

D;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N

REVEL

Uncertain

0.59

Sift

Uncertain

0.0020

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

Sift4G

Pathogenic

0.0

D;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

Polyphen

0.95, 0.98, 0.99, 1.0, 0.99

.;.;P;.;D;P;D;P;D;D;D;P;D;D;P;P;D;.;P;D;.;.;.;.

Vest4

0.73, 0.61, 0.69, 0.62, 0.59, 0.61, 0.59, 0.59, 0.61, 0.69, 0.63, 0.60, 0.63, 0.58, 0.59, 0.71, 0.60, 0.67, 0.59, 0.61, 0.60, 0.72

MutPred

0.40

.;Gain of catalytic residue at Y20 (P = 0);Gain of catalytic residue at Y20 (P = 0);Gain of catalytic residue at Y20 (P = 0);Gain of catalytic residue at Y20 (P = 0);Gain of catalytic residue at Y20 (P = 0);Gain of catalytic residue at Y20 (P = 0);Gain of catalytic residue at Y20 (P = 0);Gain of catalytic residue at Y20 (P = 0);Gain of catalytic residue at Y20 (P = 0);Gain of catalytic residue at Y20 (P = 0);Gain of catalytic residue at Y20 (P = 0);Gain of catalytic residue at Y20 (P = 0);Gain of catalytic residue at Y20 (P = 0);Gain of catalytic residue at Y20 (P = 0);Gain of catalytic residue at Y20 (P = 0);Gain of catalytic residue at Y20 (P = 0);Gain of catalytic residue at Y20 (P = 0);Gain of catalytic residue at Y20 (P = 0);Gain of catalytic residue at Y20 (P = 0);Gain of catalytic residue at Y20 (P = 0);Gain of catalytic residue at Y20 (P = 0);Gain of catalytic residue at Y20 (P = 0);Gain of catalytic residue at Y20 (P = 0);

MVP

0.84

MPC

2.1

ClinPred

0.50

GERP RS

5.8

gMVP

0.71

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over