rs186867242

Variant names:

• chr12-2686232-A-G
• rs186867242
• NM_000719.7:c.5747A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000719.7(CACNA1C):​c.5747A>G​(p.Gln1916Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000169 in 1,613,314 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 5.70
• Publications: 10 publications found

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]

ITFG2-AS1 (HGNC:53128): (ITFG2 antisense RNA 1)

CACNA1C-AS1 (HGNC:40119): (CACNA1C antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014277607).
• BP6: Variant 12-2686232-A-G is Benign according to our data. Variant chr12-2686232-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 263515.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000164 (25/152356) while in subpopulation EAS AF = 0.00463 (24/5188). AF 95% confidence interval is 0.00319. There are 0 homozygotes in GnomAd4. There are 12 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 25 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.5747A>G	p.Gln1916Arg	missense_variant	Exon 45 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.5747A>G	p.Gln1916Arg	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.5747A>G	p.Gln1916Arg	missense_variant	Exon 45 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.5747A>G	p.Gln1916Arg	missense_variant	Exon 45 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.6086A>G	p.Gln2029Arg	missense_variant	Exon 48 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.5960A>G	p.Gln1987Arg	missense_variant	Exon 46 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.5927A>G	p.Gln1976Arg	missense_variant	Exon 45 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.5912A>G	p.Gln1971Arg	missense_variant	Exon 46 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.5891A>G	p.Gln1964Arg	missense_variant	Exon 47 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.5870A>G	p.Gln1957Arg	missense_variant	Exon 45 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.5852A>G	p.Gln1951Arg	missense_variant	Exon 46 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.5852A>G	p.Gln1951Arg	missense_variant	Exon 46 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.5837A>G	p.Gln1946Arg	missense_variant	Exon 45 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.5837A>G	p.Gln1946Arg	missense_variant	Exon 45 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.5837A>G	p.Gln1946Arg	missense_variant	Exon 45 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.5837A>G	p.Gln1946Arg	missense_variant	Exon 45 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.5831A>G	p.Gln1944Arg	missense_variant	Exon 46 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.5822A>G	p.Gln1941Arg	missense_variant	Exon 46 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.5807A>G	p.Gln1936Arg	missense_variant	Exon 46 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.5804A>G	p.Gln1935Arg	missense_variant	Exon 45 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.5804A>G	p.Gln1935Arg	missense_variant	Exon 45 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.5804A>G	p.Gln1935Arg	missense_variant	Exon 45 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.5798A>G	p.Gln1933Arg	missense_variant	Exon 45 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.5789A>G	p.Gln1930Arg	missense_variant	Exon 45 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.5771A>G	p.Gln1924Arg	missense_variant	Exon 44 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.5771A>G	p.Gln1924Arg	missense_variant	Exon 44 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.5765A>G	p.Gln1922Arg	missense_variant	Exon 44 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.5747A>G	p.Gln1916Arg	missense_variant	Exon 45 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.5747A>G	p.Gln1916Arg	missense_variant	Exon 45 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.5747A>G	p.Gln1916Arg	missense_variant	Exon 45 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.5747A>G	p.Gln1916Arg	missense_variant	Exon 45 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.5747A>G	p.Gln1916Arg	missense_variant	Exon 45 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.5738A>G	p.Gln1913Arg	missense_variant	Exon 45 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.5714A>G	p.Gln1905Arg	missense_variant	Exon 44 of 46			ENSP00000507309.1

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152238 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00462

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000221 AC: 55 AN: 249300 AF XY: 0.000222

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00295

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000330

GnomAD4 exome AF: 0.000169 AC: 247 AN: 1460958 Hom.: 0 Cov.: 32 AF XY: 0.000165 AC XY: 120 AN XY: 726800

African (AFR) AF: 0.00 AC: 0 AN: 33464

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00599 AC: 238 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86216

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5208

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111816

Other (OTH) AF: 0.0000829 AC: 5 AN: 60294

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152356 Hom.: 0 Cov.: 33 AF XY: 0.000161 AC XY: 12 AN XY: 74514

African (AFR) AF: 0.00 AC: 0 AN: 41580

American (AMR) AF: 0.00 AC: 0 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00463 AC: 24 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68028

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000130 Hom.: 0

Bravo AF: 0.000121

ExAC AF: 0.000149 AC: 18

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Feb 25, 2019

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The variant, CACNA1C c.5747A>G (p.Gln1916Arg) results in a conservative amino acid change located in the Voltage-gated calcium channel subunit alpha, C-terminal domain 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 0.00021 in 277978 control chromosomes, predominantly at a frequency of 0.0029 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 290 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.5747A>G has been reported in the literature in individuals affected with sudden cardiac death, sudden unexplained death syndrome and congenital long-QT syndrome (Liu_2017, Hata_2016, Chae_2017) including one large family study that showed incomplete penetrance for the variant. However, all these studies were of the same ethnic compoisition as seen in the control databases. Therefore, these reports do not provide unequivocal evidence supporting a deleterious outcome. Electrophysiological experiments using CACNA1C-Q1916R protein showed a reduction in amplitude of the current produced by the L-type calcium channel current. Moreover, in a human ventricular cell model used to stimulate action potential of endocardium and epicardium, the variant showed a 30% reduction in the conductance of the total ICa-L and AP duration at the level of 90% repolarization was reduced by 14.29% compared to WT (Liu_2017). A ClinVar submissions from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as likely benign, however, this was submitted prior to the Liu_2017 publication. Based on the evidence outlined above, the variant was classified as VUS - possibly benign. -

Long QT syndrome Benign:1

Dec 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Apr 11, 2017

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
CardioboostArm	Benign	0.0000035
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.022	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.;T
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.014	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.91	T
PhyloP100		5.7
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.7	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;.
REVEL	Benign	0.15
Sift	Benign	0.15	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;D;T;D;.
Sift4G	Benign	0.69	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.49, 0.55, 0.23, 0.082, 0.35, 0.60, 0.28, 0.30, 0.45, 0.73, 0.63	.;P;P;B;B;B;P;P;B;B;P;P;B;P;P;.;P;P;.;.;.;P;.
Vest4		0.73
MVP		0.71
MPC		0.32
ClinPred		0.070	T
GERP RS		4.8
gMVP		0.60
Mutation Taster		=87/13	polymorphism

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

Other links and lift over

dbSNP: rs186867242; hg19: chr12-2795398; COSMIC: COSV59708445; COSMIC: COSV59708445;