12-2115244-C-T

Position:

• chr12-2115244-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2 BS2

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 (★★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 3.65

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CACNA1C. . Gene score misZ 6.4654 (greater than the threshold 3.09). Trascript score misZ 7.2674 (greater than threshold 3.09). GenCC has associacion of gene with 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 21 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.70C>T	p.Arg24Cys	missense_variant	2/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.70C>T	p.Arg24Cys	missense_variant	2/47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.70C>T	p.Arg24Cys	missense_variant	2/47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.70C>T	p.Arg24Cys	missense_variant	2/47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.160C>T	p.Arg54Cys	missense_variant	2/50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.70C>T	p.Arg24Cys	missense_variant	2/48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.70C>T	p.Arg24Cys	missense_variant	2/47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.160C>T	p.Arg54Cys	missense_variant	2/48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.70C>T	p.Arg24Cys	missense_variant	2/49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.70C>T	p.Arg24Cys	missense_variant	2/47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.70C>T	p.Arg24Cys	missense_variant	2/48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.70C>T	p.Arg24Cys	missense_variant	2/48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.160C>T	p.Arg54Cys	missense_variant	2/47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.160C>T	p.Arg54Cys	missense_variant	2/47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.160C>T	p.Arg54Cys	missense_variant	2/47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.160C>T	p.Arg54Cys	missense_variant	2/47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.70C>T	p.Arg24Cys	missense_variant	2/48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.70C>T	p.Arg24Cys	missense_variant	2/48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.70C>T	p.Arg24Cys	missense_variant	2/48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.70C>T	p.Arg24Cys	missense_variant	2/47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.70C>T	p.Arg24Cys	missense_variant	2/47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.70C>T	p.Arg24Cys	missense_variant	2/47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.70C>T	p.Arg24Cys	missense_variant	2/47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.70C>T	p.Arg24Cys	missense_variant	2/47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.70C>T	p.Arg24Cys	missense_variant	2/46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.70C>T	p.Arg24Cys	missense_variant	2/46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.70C>T	p.Arg24Cys	missense_variant	2/46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.70C>T	p.Arg24Cys	missense_variant	2/47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.70C>T	p.Arg24Cys	missense_variant	2/47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.70C>T	p.Arg24Cys	missense_variant	2/47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.70C>T	p.Arg24Cys	missense_variant	2/47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.70C>T	p.Arg24Cys	missense_variant	2/47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.70C>T	p.Arg24Cys	missense_variant	2/47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.70C>T	p.Arg24Cys	missense_variant	2/46			ENSP00000507309.1
CACNA1C	ENST00000682152.1	c.19C>T	p.Arg7Cys	missense_variant	1/6			ENSP00000506759.1
CACNA1C	ENST00000480911.6	n.70C>T		non_coding_transcript_exon_variant	2/27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152272 Hom.: 0 Cov.: 34

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: 21 AN: 1425972 Hom.: 0 Cov.: 31 AF XY: 0.0000184 AC XY: 13 AN XY: 704752

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: 3 AN: 152272 Hom.: 0 Cov.: 34 AF XY: 0.0000134 AC XY: 1 AN XY: 74394

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: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

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

Labcorp Genetics (formerly Invitae), Labcorp

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
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.020	.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.89	D
M_CAP	Benign	0.064	D
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	D
MutationAssessor	Benign	0.0	.;.;N;.;N;N;N;N;N;N;N;N;N;N;N;N;N;.;N;N;N;.;.;.
PrimateAI	Uncertain	0.77	T
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	D
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

Other links and lift over

dbSNP: rs773211348; hg19: chr12-2224410;