rs41276710

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000719.7(CACNA1C):c.4485T>C(p.Asp1495Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00979 in 1,613,432 control chromosomes in the GnomAD database, including 701 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.039 ( 350 hom., cov: 32)

Exomes 𝑓: 0.0067 ( 351 hom. )

Consequence

CACNA1C
NM_000719.7 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.470

Publications

4 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.48).

BP6

Variant 12-2665667-T-C is Benign according to our data. Variant chr12-2665667-T-C is described in ClinVar as Benign. ClinVar VariationId is 93407.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.47 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.126 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7 link	c.4485T>C	p.Asp1495Asp	synonymous_variant	Exon 36 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2 link	c.4485T>C	p.Asp1495Asp	synonymous_variant	Exon 36 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CACNA1C	ENST00000399603.6 link	c.4485T>C	p.Asp1495Asp	synonymous_variant	Exon 36 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6 link	c.4485T>C	p.Asp1495Asp	synonymous_variant	Exon 36 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1 link	c.4719T>C	p.Asp1573Asp	synonymous_variant	Exon 38 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8 link	c.4485T>C	p.Asp1495Asp	synonymous_variant	Exon 36 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6 link	c.4452T>C	p.Asp1484Asp	synonymous_variant	Exon 35 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1 link	c.4650T>C	p.Asp1550Asp	synonymous_variant	Exon 37 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9 link	c.4629T>C	p.Asp1543Asp	synonymous_variant	Exon 38 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7 link	c.4551T>C	p.Asp1517Asp	synonymous_variant	Exon 36 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12 link	c.4485T>C	p.Asp1495Asp	synonymous_variant	Exon 36 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6 link	c.4485T>C	p.Asp1495Asp	synonymous_variant	Exon 36 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1 link	c.4575T>C	p.Asp1525Asp	synonymous_variant	Exon 36 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1 link	c.4575T>C	p.Asp1525Asp	synonymous_variant	Exon 36 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1 link	c.4575T>C	p.Asp1525Asp	synonymous_variant	Exon 36 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1 link	c.4575T>C	p.Asp1525Asp	synonymous_variant	Exon 36 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5 link	c.4569T>C	p.Asp1523Asp	synonymous_variant	Exon 37 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10 link	c.4560T>C	p.Asp1520Asp	synonymous_variant	Exon 37 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5 link	c.4545T>C	p.Asp1515Asp	synonymous_variant	Exon 37 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5 link	c.4485T>C	p.Asp1495Asp	synonymous_variant	Exon 36 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5 link	c.4485T>C	p.Asp1495Asp	synonymous_variant	Exon 36 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7 link	c.4485T>C	p.Asp1495Asp	synonymous_variant	Exon 36 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5 link	c.4536T>C	p.Asp1512Asp	synonymous_variant	Exon 36 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1 link	c.4527T>C	p.Asp1509Asp	synonymous_variant	Exon 36 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5 link	c.4452T>C	p.Asp1484Asp	synonymous_variant	Exon 35 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5 link	c.4452T>C	p.Asp1484Asp	synonymous_variant	Exon 35 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5 link	c.4446T>C	p.Asp1482Asp	synonymous_variant	Exon 35 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5 link	c.4485T>C	p.Asp1495Asp	synonymous_variant	Exon 36 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5 link	c.4485T>C	p.Asp1495Asp	synonymous_variant	Exon 36 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6 link	c.4485T>C	p.Asp1495Asp	synonymous_variant	Exon 36 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5 link	c.4485T>C	p.Asp1495Asp	synonymous_variant	Exon 36 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1 link	c.4485T>C	p.Asp1495Asp	synonymous_variant	Exon 36 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1 link	c.4476T>C	p.Asp1492Asp	synonymous_variant	Exon 36 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1 link	c.4452T>C	p.Asp1484Asp	synonymous_variant	Exon 35 of 46			ENSP00000507309.1

Frequencies

GnomAD3 genomes

AF:

0.0390

AC:

5938

AN:

152092

Hom.:

348

Cov.:

show subpopulations

Gnomad AFR

AF:

0.129

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0149

Gnomad ASJ

AF:

0.00230

Gnomad EAS

AF:

0.000579

Gnomad SAS

AF:

0.0102

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00348

Gnomad OTH

AF:

0.0292

GnomAD2 exomes

AF:

0.0122

AC:

3039

AN:

249384

AF XY:

0.0102

show subpopulations

Gnomad AFR exome

AF:

0.135

Gnomad AMR exome

AF:

0.00858

Gnomad ASJ exome

AF:

0.00159

Gnomad EAS exome

AF:

0.000442

Gnomad FIN exome

AF:

0.0000928

Gnomad NFE exome

AF:

0.00319

Gnomad OTH exome

AF:

0.00595

GnomAD4 exome

AF:

0.00673

AC:

9839

AN:

1461222

Hom.:

351

Cov.:

AF XY:

0.00652

AC XY:

4739

AN XY:

726914

show subpopulations

African (AFR)

AF:

0.141

AC:

4730

AN:

33466

American (AMR)

AF:

0.00897

AC:

401

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.00149

AC:

AN:

26122

East Asian (EAS)

AF:

0.000252

AC:

AN:

39690

South Asian (SAS)

AF:

0.00820

AC:

707

AN:

86246

European-Finnish (FIN)

AF:

0.000206

AC:

AN:

53376

Middle Eastern (MID)

AF:

0.0141

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00284

AC:

3162

AN:

1111504

Other (OTH)

AF:

0.0116

AC:

698

AN:

60346

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

420

839

1259

1678

2098

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

216

432

648

864

1080

<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:

0.0391

AC:

5953

AN:

152210

Hom.:

350

Cov.:

AF XY:

0.0378

AC XY:

2813

AN XY:

74432

show subpopulations

African (AFR)

AF:

0.129

AC:

5364

AN:

41514

American (AMR)

AF:

0.0148

AC:

227

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00230

AC:

AN:

3472

East Asian (EAS)

AF:

0.000580

AC:

AN:

5168

South Asian (SAS)

AF:

0.00996

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00348

AC:

237

AN:

68008

Other (OTH)

AF:

0.0289

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

270

540

810

1080

1350

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.0181

Hom.:

123

Bravo

AF:

0.0445

Asia WGS

AF:

0.0110

AC:

AN:

3478

EpiCase

AF:

0.00360

EpiControl

AF:

0.00445

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 23, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Long QT syndrome

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Jun 26, 2015

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.48

CADD

Benign

6.2

(source)

DANN

Benign

0.84

PhyloP100

0.47

Mutation Taster

=93/7

polymorphism (auto)

(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