rs188224114

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_000719.7(CACNA1C):c.3387G>A(p.Thr1129Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00112 in 1,612,720 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0048 ( 8 hom., cov: 32)

Exomes 𝑓: 0.00075 ( 9 hom. )

Consequence

CACNA1C
NM_000719.7 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.806

Publications

2 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=-0.79).

BP6

Variant 12-2608541-G-A is Benign according to our data. Variant chr12-2608541-G-A is described in ClinVar as Benign. ClinVar VariationId is 78960.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.806 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00476 (725/152270) while in subpopulation AFR AF = 0.0159 (660/41552). AF 95% confidence interval is 0.0149. There are 8 homozygotes in GnomAd4. There are 327 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 725 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7 link	c.3387G>A	p.Thr1129Thr	synonymous_variant	Exon 27 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2 link	c.3387G>A	p.Thr1129Thr	synonymous_variant	Exon 27 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CACNA1C	ENST00000399603.6 link	c.3387G>A	p.Thr1129Thr	synonymous_variant	Exon 27 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6 link	c.3387G>A	p.Thr1129Thr	synonymous_variant	Exon 27 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1 link	c.3537G>A	p.Thr1179Thr	synonymous_variant	Exon 28 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8 link	c.3387G>A	p.Thr1129Thr	synonymous_variant	Exon 27 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6 link	c.3387G>A	p.Thr1129Thr	synonymous_variant	Exon 27 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1 link	c.3552G>A	p.Thr1184Thr	synonymous_variant	Exon 28 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9 link	c.3447G>A	p.Thr1149Thr	synonymous_variant	Exon 28 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7 link	c.3387G>A	p.Thr1129Thr	synonymous_variant	Exon 27 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12 link	c.3387G>A	p.Thr1129Thr	synonymous_variant	Exon 27 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6 link	c.3387G>A	p.Thr1129Thr	synonymous_variant	Exon 27 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1 link	c.3477G>A	p.Thr1159Thr	synonymous_variant	Exon 27 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1 link	c.3477G>A	p.Thr1159Thr	synonymous_variant	Exon 27 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1 link	c.3477G>A	p.Thr1159Thr	synonymous_variant	Exon 27 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1 link	c.3477G>A	p.Thr1159Thr	synonymous_variant	Exon 27 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5 link	c.3387G>A	p.Thr1129Thr	synonymous_variant	Exon 27 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10 link	c.3462G>A	p.Thr1154Thr	synonymous_variant	Exon 28 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5 link	c.3447G>A	p.Thr1149Thr	synonymous_variant	Exon 28 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5 link	c.3387G>A	p.Thr1129Thr	synonymous_variant	Exon 27 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5 link	c.3387G>A	p.Thr1129Thr	synonymous_variant	Exon 27 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7 link	c.3387G>A	p.Thr1129Thr	synonymous_variant	Exon 27 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5 link	c.3387G>A	p.Thr1129Thr	synonymous_variant	Exon 27 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1 link	c.3462G>A	p.Thr1154Thr	synonymous_variant	Exon 28 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5 link	c.3387G>A	p.Thr1129Thr	synonymous_variant	Exon 27 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5 link	c.3387G>A	p.Thr1129Thr	synonymous_variant	Exon 27 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5 link	c.3387G>A	p.Thr1129Thr	synonymous_variant	Exon 27 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5 link	c.3387G>A	p.Thr1129Thr	synonymous_variant	Exon 27 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5 link	c.3387G>A	p.Thr1129Thr	synonymous_variant	Exon 27 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6 link	c.3387G>A	p.Thr1129Thr	synonymous_variant	Exon 27 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5 link	c.3387G>A	p.Thr1129Thr	synonymous_variant	Exon 27 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1 link	c.3387G>A	p.Thr1129Thr	synonymous_variant	Exon 27 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1 link	c.3378G>A	p.Thr1126Thr	synonymous_variant	Exon 27 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1 link	c.3387G>A	p.Thr1129Thr	synonymous_variant	Exon 27 of 46			ENSP00000507309.1
CACNA1C	ENST00000480911.6 link	n.*1994G>A		non_coding_transcript_exon_variant	Exon 25 of 27	5		ENSP00000437936.2
CACNA1C	ENST00000480911.6 link	n.*1994G>A		3_prime_UTR_variant	Exon 25 of 27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes

AF:

0.00475

AC:

723

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0159

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00118

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000500

Gnomad OTH

AF:

0.00383

GnomAD2 exomes

AF:

0.00166

AC:

413

AN:

248434

AF XY:

0.00129

show subpopulations

Gnomad AFR exome

AF:

0.0162

Gnomad AMR exome

AF:

0.00233

Gnomad ASJ exome

AF:

0.000400

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000929

Gnomad NFE exome

AF:

0.000499

Gnomad OTH exome

AF:

0.00181

GnomAD4 exome

AF:

0.000746

AC:

1089

AN:

1460450

Hom.:

Cov.:

AF XY:

0.000625

AC XY:

454

AN XY:

726356

show subpopulations

African (AFR)

AF:

0.0185

AC:

618

AN:

33450

American (AMR)

AF:

0.00209

AC:

AN:

44530

Ashkenazi Jewish (ASJ)

AF:

0.000153

AC:

AN:

26094

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39650

South Asian (SAS)

AF:

0.0000698

AC:

AN:

85956

European-Finnish (FIN)

AF:

0.0000375

AC:

AN:

53316

Middle Eastern (MID)

AF:

0.00139

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000252

AC:

280

AN:

1111338

Other (OTH)

AF:

0.00128

AC:

AN:

60348

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

111

166

222

277

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

<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:

0.00476

AC:

725

AN:

152270

Hom.:

Cov.:

AF XY:

0.00439

AC XY:

327

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.0159

AC:

660

AN:

41552

American (AMR)

AF:

0.00118

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000500

AC:

AN:

68022

Other (OTH)

AF:

0.00379

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

115

153

191

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:

0.00265

Hom.:

Bravo

AF:

0.00556

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jul 29, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

Nov 09, 2015

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:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

CACNA1C-related disorder

Benign:1

Jan 13, 2020

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 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Jun 14, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

4.0

(source)

DANN

Benign

0.86

PhyloP100

-0.81

Mutation Taster

=93/7

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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