rs112414325

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000719.7(CACNA1C):c.5918G>A(p.Arg1973Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0023 in 1,613,954 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1973W) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0020 ( 3 hom., cov: 33)

Exomes 𝑓: 0.0023 ( 36 hom. )

Consequence

CACNA1C
NM_000719.7 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:16

Conservation

PhyloP100: 2.58

Publications

20 publications found

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:

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

ITFG2-AS1 links:

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

CACNA1C-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006121576).

BP6

Variant 12-2688580-G-A is Benign according to our data. Variant chr12-2688580-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 93419.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00195 (297/152296) while in subpopulation SAS AF = 0.018 (87/4826). AF 95% confidence interval is 0.015. There are 3 homozygotes in GnomAd4. There are 170 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 297 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7 link	c.5918G>A	p.Arg1973Gln	missense_variant	Exon 46 of 47	ENST00000399655.6	NP_000710.5	Q13936-12
CACNA1C	NM_001167623.2 link	c.5918G>A	p.Arg1973Gln	missense_variant	Exon 46 of 47	ENST00000399603.6	NP_001161095.1	Q13936-37

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CACNA1C	ENST00000399603.6 link	c.5918G>A	p.Arg1973Gln	missense_variant	Exon 46 of 47	5	NM_001167623.2	ENSP00000382512.1	Q13936-37
CACNA1C	ENST00000399655.6 link	c.5918G>A	p.Arg1973Gln	missense_variant	Exon 46 of 47	1	NM_000719.7	ENSP00000382563.1	Q13936-12
CACNA1C	ENST00000682544.1 link	c.6257G>A	p.Arg2086Gln	missense_variant	Exon 49 of 50			ENSP00000507184.1	A0A804HIR0
CACNA1C	ENST00000406454.8 link	c.6131G>A	p.Arg2044Gln	missense_variant	Exon 47 of 48	5		ENSP00000385896.3	F5GY28
CACNA1C	ENST00000399634.6 link	c.6098G>A	p.Arg2033Gln	missense_variant	Exon 46 of 47	5		ENSP00000382542.2	E9PDI6
CACNA1C	ENST00000683824.1 link	c.6083G>A	p.Arg2028Gln	missense_variant	Exon 47 of 48			ENSP00000507867.1	A0A804HKC4
CACNA1C	ENST00000347598.9 link	c.6062G>A	p.Arg2021Gln	missense_variant	Exon 48 of 49	1		ENSP00000266376.6	Q13936-11
CACNA1C	ENST00000344100.7 link	c.6041G>A	p.Arg2014Gln	missense_variant	Exon 46 of 47	1		ENSP00000341092.3	Q13936-14
CACNA1C	ENST00000327702.12 link	c.6023G>A	p.Arg2008Gln	missense_variant	Exon 47 of 48	1		ENSP00000329877.7	A0A0A0MR67
CACNA1C	ENST00000399617.6 link	c.6023G>A	p.Arg2008Gln	missense_variant	Exon 47 of 48	5		ENSP00000382526.1	A0A0A0MSA1
CACNA1C	ENST00000682462.1 link	c.6008G>A	p.Arg2003Gln	missense_variant	Exon 46 of 47			ENSP00000507105.1	A0A804HIJ8
CACNA1C	ENST00000683781.1 link	c.6008G>A	p.Arg2003Gln	missense_variant	Exon 46 of 47			ENSP00000507434.1	A0A804HJB6
CACNA1C	ENST00000683840.1 link	c.6008G>A	p.Arg2003Gln	missense_variant	Exon 46 of 47			ENSP00000507612.1	A0A804HJR1
CACNA1C	ENST00000683956.1 link	c.6008G>A	p.Arg2003Gln	missense_variant	Exon 46 of 47			ENSP00000506882.1	A0A804HI37
CACNA1C	ENST00000399638.5 link	c.6002G>A	p.Arg2001Gln	missense_variant	Exon 47 of 48	1		ENSP00000382547.1	Q13936-31
CACNA1C	ENST00000335762.10 link	c.5993G>A	p.Arg1998Gln	missense_variant	Exon 47 of 48	5		ENSP00000336982.5	F5H522
CACNA1C	ENST00000399606.5 link	c.5978G>A	p.Arg1993Gln	missense_variant	Exon 47 of 48	1		ENSP00000382515.1	Q13936-30
CACNA1C	ENST00000399621.5 link	c.5975G>A	p.Arg1992Gln	missense_variant	Exon 46 of 47	1		ENSP00000382530.1	Q13936-24
CACNA1C	ENST00000399637.5 link	c.5975G>A	p.Arg1992Gln	missense_variant	Exon 46 of 47	1		ENSP00000382546.1	Q13936-27
CACNA1C	ENST00000402845.7 link	c.5975G>A	p.Arg1992Gln	missense_variant	Exon 46 of 47	1		ENSP00000385724.3	Q13936-13
CACNA1C	ENST00000399629.5 link	c.5969G>A	p.Arg1990Gln	missense_variant	Exon 46 of 47	1		ENSP00000382537.1	Q13936-32
CACNA1C	ENST00000682336.1 link	c.5960G>A	p.Arg1987Gln	missense_variant	Exon 46 of 47			ENSP00000507898.1	A0A804HKE9
CACNA1C	ENST00000399591.5 link	c.5942G>A	p.Arg1981Gln	missense_variant	Exon 45 of 46	1		ENSP00000382500.1	Q13936-29
CACNA1C	ENST00000399595.5 link	c.5942G>A	p.Arg1981Gln	missense_variant	Exon 45 of 46	1		ENSP00000382504.1	Q13936-25
CACNA1C	ENST00000399649.5 link	c.5936G>A	p.Arg1979Gln	missense_variant	Exon 45 of 46	1		ENSP00000382557.1	Q13936-15
CACNA1C	ENST00000399597.5 link	c.5918G>A	p.Arg1973Gln	missense_variant	Exon 46 of 47	1		ENSP00000382506.1	Q13936-22
CACNA1C	ENST00000399601.5 link	c.5918G>A	p.Arg1973Gln	missense_variant	Exon 46 of 47	1		ENSP00000382510.1	Q13936-20
CACNA1C	ENST00000399641.6 link	c.5918G>A	p.Arg1973Gln	missense_variant	Exon 46 of 47	1		ENSP00000382549.1	Q13936-23
CACNA1C	ENST00000399644.5 link	c.5918G>A	p.Arg1973Gln	missense_variant	Exon 46 of 47	1		ENSP00000382552.1	Q13936-21
CACNA1C	ENST00000682835.1 link	c.5918G>A	p.Arg1973Gln	missense_variant	Exon 46 of 47			ENSP00000507282.1	A0A804HIZ0
CACNA1C	ENST00000683482.1 link	c.5909G>A	p.Arg1970Gln	missense_variant	Exon 46 of 47			ENSP00000507169.1	Q13936-35
CACNA1C	ENST00000682686.1 link	c.5885G>A	p.Arg1962Gln	missense_variant	Exon 45 of 46			ENSP00000507309.1	Q13936-19

Frequencies

GnomAD3 genomes

AF:

0.00195

AC:

296

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000410

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00177

Gnomad ASJ

AF:

0.0135

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0178

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00156

Gnomad OTH

AF:

0.00430

GnomAD2 exomes

AF:

0.00345

AC:

857

AN:

248420

AF XY:

0.00425

show subpopulations

Gnomad AFR exome

AF:

0.0000649

Gnomad AMR exome

AF:

0.00127

Gnomad ASJ exome

AF:

0.0126

Gnomad EAS exome

AF:

0.0000557

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.00167

Gnomad OTH exome

AF:

0.00414

GnomAD4 exome

AF:

0.00234

AC:

3418

AN:

1461658

Hom.:

Cov.:

AF XY:

0.00276

AC XY:

2004

AN XY:

727118

show subpopulations

African (AFR)

AF:

0.000209

AC:

AN:

33480

American (AMR)

AF:

0.00141

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0127

AC:

332

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0156

AC:

1345

AN:

86252

European-Finnish (FIN)

AF:

0.0000562

AC:

AN:

53354

Middle Eastern (MID)

AF:

0.00798

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00126

AC:

1403

AN:

1111870

Other (OTH)

AF:

0.00363

AC:

219

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

224

448

671

895

1119

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

124

186

248

310

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00195

AC:

297

AN:

152296

Hom.:

Cov.:

AF XY:

0.00228

AC XY:

170

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.000409

AC:

AN:

41562

American (AMR)

AF:

0.00176

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.0135

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5170

South Asian (SAS)

AF:

0.0180

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00156

AC:

106

AN:

68018

Other (OTH)

AF:

0.00426

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00212

Hom.:

Bravo

AF:

0.00153

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000518

AC:

ESP6500EA

AF:

0.00218

AC:

ExAC

AF:

0.00357

AC:

431

Asia WGS

AF:

0.00318

AC:

AN:

3478

EpiCase

AF:

0.00185

EpiControl

AF:

0.00172

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:9

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 20, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CACNA1C: PM5, BP4, BS1, BS2 -

Jan 25, 2016

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: CACNA1C c.5918G>A affects a conserved nucleotide, resulting in amino acid change from Arg to Gln. 3/4 in-silico tools predict this variant to be benign. This variant is found in 433/121010 control chromosomes including the large and broad populations from ExAC at a frequency of 0.0035782, which is about 358 times greater than the maximal expected frequency of a pathogenic allele (0.00001) in this gene, suggesting this variant is benign. Five homozygotes were reported in ExAC. This variant has been reported in multiple LQTS and BrS patients without strong evidence for causality (eg. co-segregation studies). Clinical diagnostic labs have classified this variant as a VUS or likely benign before the large and diverse ExAC control cohorts were available. Taken together, this variant was classified as likely benign. -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Uncertain:1Benign:3

Dec 02, 2014

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. Based on the data reviewed we consider this a variant of uncertain significance. This variant is novel. Pathogenic variants in CACNA1C are associated with Timothy syndrome and Brugada syndrome. This is a semi-conservative amino acid change with a hydrophilic basic polar Arginine replaced with a hydrophilic polar Glutamine. The variant is found in a highly conserved region of the CACNA1C gene. The reporting lab observed the variant in 2 out of 353 presumably healthy individuals of mixed ethnic background. Based on these data it is currently unclear whether this variant can cause disease, however given the presence in controls for a variant in a gene thus far only associated with quite rare diseases, it seems most likely that this variant does not cause rare Mendelian disease such as long QT syndrome. -

Jun 21, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 10, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

CACNA1C-related disorder

Benign:1

Sep 17, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Long QT syndrome

Benign:1

Jan 25, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Jun 27, 2016

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as 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. -

Short QT syndrome

Benign:1

Oct 14, 2014

Blueprint Genetics

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.098

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.33

CADD

Benign

(source)

DANN

Benign

0.83

DEOGEN2

Benign

0.0053

T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.;T

Eigen

Benign

-0.31

Eigen_PC

Benign

-0.16

FATHMM_MKL

Uncertain

0.96

MetaRNN

Benign

0.0061

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

-0.94

PhyloP100

2.6

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.51

N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;.

REVEL

Benign

0.18

Sift

Benign

0.48

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;.

Sift4G

Benign

0.59

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

Polyphen

0.032, 0.0070, 0.014, 0.0060, 0.086, 0.049, 0.083, 0.10, 0.98, 0.028

.;B;B;B;B;B;B;B;B;B;B;B;B;D;B;.;B;B;.;.;.;B;.

Vest4

0.32

MVP

0.77

MPC

0.22

ClinPred

0.013

GERP RS

5.0

gMVP

0.43

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.12

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over