rs139842134

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBS1BS2

The NM_000719.7(CACNA1C):c.1074G>A(p.Gln358Gln) variant causes a synonymous change. The variant allele was found at a frequency of 0.000178 in 1,614,176 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0010 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000088 ( 0 hom. )

Consequence

CACNA1C
NM_000719.7 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 5.96

Publications

0 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 Gene-Disease associations (from GenCC):

Timothy syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, G2P, Labcorp Genetics (formerly Invitae)
neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizures
Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
long QT syndrome
Inheritance: AD Classification: MODERATE Submitted by: ClinGen
long QT syndrome 8
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
Brugada syndrome
Inheritance: AD Classification: SUPPORTIVE, NO_KNOWN Submitted by: Orphanet, ClinGen
Brugada syndrome 3
Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
intellectual disability
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
short QT syndrome
Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Ambry Genetics, ClinGen

CACNA1C links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.39).

BP6

Variant 12-2493347-G-A is Benign according to our data. Variant chr12-2493347-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 238170.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00104 (158/152348) while in subpopulation AFR AF = 0.00358 (149/41582). AF 95% confidence interval is 0.00311. There are 0 homozygotes in GnomAd4. There are 69 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 158 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7 link	c.1074G>A	p.Gln358Gln	synonymous_variant	Exon 7 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2 link	c.1074G>A	p.Gln358Gln	synonymous_variant	Exon 7 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CACNA1C	ENST00000399603.6 link	c.1074G>A	p.Gln358Gln	synonymous_variant	Exon 7 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6 link	c.1074G>A	p.Gln358Gln	synonymous_variant	Exon 7 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1 link	c.1164G>A	p.Gln388Gln	synonymous_variant	Exon 7 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8 link	c.1074G>A	p.Gln358Gln	synonymous_variant	Exon 7 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6 link	c.1074G>A	p.Gln358Gln	synonymous_variant	Exon 7 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1 link	c.1164G>A	p.Gln388Gln	synonymous_variant	Exon 7 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9 link	c.1074G>A	p.Gln358Gln	synonymous_variant	Exon 7 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7 link	c.1074G>A	p.Gln358Gln	synonymous_variant	Exon 7 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12 link	c.1074G>A	p.Gln358Gln	synonymous_variant	Exon 7 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6 link	c.1074G>A	p.Gln358Gln	synonymous_variant	Exon 7 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1 link	c.1164G>A	p.Gln388Gln	synonymous_variant	Exon 7 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1 link	c.1164G>A	p.Gln388Gln	synonymous_variant	Exon 7 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1 link	c.1164G>A	p.Gln388Gln	synonymous_variant	Exon 7 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1 link	c.1164G>A	p.Gln388Gln	synonymous_variant	Exon 7 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5 link	c.1074G>A	p.Gln358Gln	synonymous_variant	Exon 7 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10 link	c.1074G>A	p.Gln358Gln	synonymous_variant	Exon 7 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5 link	c.1074G>A	p.Gln358Gln	synonymous_variant	Exon 7 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5 link	c.1074G>A	p.Gln358Gln	synonymous_variant	Exon 7 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5 link	c.1074G>A	p.Gln358Gln	synonymous_variant	Exon 7 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7 link	c.1074G>A	p.Gln358Gln	synonymous_variant	Exon 7 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5 link	c.1074G>A	p.Gln358Gln	synonymous_variant	Exon 7 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1 link	c.1074G>A	p.Gln358Gln	synonymous_variant	Exon 7 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5 link	c.1074G>A	p.Gln358Gln	synonymous_variant	Exon 7 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5 link	c.1074G>A	p.Gln358Gln	synonymous_variant	Exon 7 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5 link	c.1074G>A	p.Gln358Gln	synonymous_variant	Exon 7 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5 link	c.1074G>A	p.Gln358Gln	synonymous_variant	Exon 7 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5 link	c.1074G>A	p.Gln358Gln	synonymous_variant	Exon 7 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6 link	c.1074G>A	p.Gln358Gln	synonymous_variant	Exon 7 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5 link	c.1074G>A	p.Gln358Gln	synonymous_variant	Exon 7 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1 link	c.1074G>A	p.Gln358Gln	synonymous_variant	Exon 7 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1 link	c.1065G>A	p.Gln355Gln	synonymous_variant	Exon 7 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1 link	c.1074G>A	p.Gln358Gln	synonymous_variant	Exon 7 of 46			ENSP00000507309.1
CACNA1C	ENST00000682152.1 link	c.1011G>A	p.Gln337Gln	synonymous_variant	Exon 6 of 6			ENSP00000506759.1
CACNA1C	ENST00000480911.6 link	n.1074G>A		non_coding_transcript_exon_variant	Exon 7 of 27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes

AF:

0.00102

AC:

155

AN:

152230

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00352

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000523

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:

0.00

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000243

AC:

AN:

250894

AF XY:

0.000133

show subpopulations

Gnomad AFR exome

AF:

0.00349

Gnomad AMR exome

AF:

0.0000868

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.0000882

AC:

129

AN:

1461828

Hom.:

Cov.:

AF XY:

0.0000688

AC XY:

AN XY:

727208

show subpopulations

African (AFR)

AF:

0.00349

AC:

117

AN:

33478

American (AMR)

AF:

0.0000894

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111962

Other (OTH)

AF:

0.000132

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.00104

AC:

158

AN:

152348

Hom.:

Cov.:

AF XY:

0.000926

AC XY:

AN XY:

74502

show subpopulations

African (AFR)

AF:

0.00358

AC:

149

AN:

41582

American (AMR)

AF:

0.000523

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68028

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.000671

Hom.:

Bravo

AF:

0.00122

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

May 18, 2015

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. -

Jul 24, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Timothy syndrome;C2678478:Brugada syndrome 3;CN260585:Long qt syndrome 8

Benign:1

Jan 21, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Mar 09, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Long QT syndrome

Benign:1

Jan 22, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Dec 14, 2016

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

BayesDel_noAF

Benign

-0.39

CADD

Benign

8.8

(source)

DANN

Benign

0.82

PhyloP100

6.0

Mutation Taster

=77/23

polymorphism

(source)

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

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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