Genetic Variant CACNA1C:p.Asp812Asp (chr12-2585472-C-T) – ACMG Classification: Benign (-21 pts)

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.2436C>T(p.Asp812Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0917 in 1,569,588 control chromosomes in the GnomAD database, including 8,146 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.093 ( 807 hom., cov: 32)

Exomes 𝑓: 0.092 ( 7339 hom. )

Consequence

CACNA1C
NM_000719.7 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.487

Publications

26 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=-0.52).

BP6

Variant 12-2585472-C-T is Benign according to our data. Variant chr12-2585472-C-T is described in ClinVar as Benign. ClinVar VariationId is 93398.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.487 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.287 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000719.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CACNA1C	NM_000719.7	MANE Select	c.2436C>T	p.Asp812Asp	synonymous	Exon 17 of 47	NP_000710.5
CACNA1C	NM_001167623.2	MANE Plus Clinical	c.2436C>T	p.Asp812Asp	synonymous	Exon 17 of 47	NP_001161095.1
CACNA1C	NM_199460.4		c.2436C>T	p.Asp812Asp	synonymous	Exon 17 of 50	NP_955630.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CACNA1C	ENST00000399603.6	TSL:5 MANE Plus Clinical	c.2436C>T	p.Asp812Asp	synonymous	Exon 17 of 47	ENSP00000382512.1
CACNA1C	ENST00000399655.6	TSL:1 MANE Select	c.2436C>T	p.Asp812Asp	synonymous	Exon 17 of 47	ENSP00000382563.1
CACNA1C	ENST00000682544.1		c.2526C>T	p.Asp842Asp	synonymous	Exon 17 of 50	ENSP00000507184.1

Frequencies

GnomAD3 genomes

AF:

0.0927

AC:

14088

AN:

152054

Hom.:

810

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0805

Gnomad AMI

AF:

0.0220

Gnomad AMR

AF:

0.0694

Gnomad ASJ

AF:

0.138

Gnomad EAS

AF:

0.300

Gnomad SAS

AF:

0.165

Gnomad FIN

AF:

0.107

Gnomad MID

AF:

0.131

Gnomad NFE

AF:

0.0804

Gnomad OTH

AF:

0.106

GnomAD2 exomes

AF:

0.111

AC:

19795

AN:

177736

AF XY:

0.115

show subpopulations

Gnomad AFR exome

AF:

0.0866

Gnomad AMR exome

AF:

0.0572

Gnomad ASJ exome

AF:

0.145

Gnomad EAS exome

AF:

0.287

Gnomad FIN exome

AF:

0.104

Gnomad NFE exome

AF:

0.0847

Gnomad OTH exome

AF:

0.107

GnomAD4 exome

AF:

0.0916

AC:

129847

AN:

1417416

Hom.:

7339

Cov.:

AF XY:

0.0942

AC XY:

66062

AN XY:

701146

show subpopulations

African (AFR)

AF:

0.0832

AC:

2726

AN:

32770

American (AMR)

AF:

0.0581

AC:

2182

AN:

37568

Ashkenazi Jewish (ASJ)

AF:

0.144

AC:

3655

AN:

25308

East Asian (EAS)

AF:

0.312

AC:

11747

AN:

37692

South Asian (SAS)

AF:

0.156

AC:

12617

AN:

80918

European-Finnish (FIN)

AF:

0.0992

AC:

5000

AN:

50398

Middle Eastern (MID)

AF:

0.130

AC:

724

AN:

5582

European-Non Finnish (NFE)

AF:

0.0782

AC:

85085

AN:

1088516

Other (OTH)

AF:

0.104

AC:

6111

AN:

58664

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

5329

10658

15988

21317

26646

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3344

6688

10032

13376

16720

<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:

0.0925

AC:

14083

AN:

152172

Hom.:

807

Cov.:

AF XY:

0.0955

AC XY:

7106

AN XY:

74378

show subpopulations

African (AFR)

AF:

0.0805

AC:

3343

AN:

41534

American (AMR)

AF:

0.0693

AC:

1060

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.138

AC:

478

AN:

3472

East Asian (EAS)

AF:

0.299

AC:

1538

AN:

5142

South Asian (SAS)

AF:

0.163

AC:

787

AN:

4820

European-Finnish (FIN)

AF:

0.107

AC:

1129

AN:

10594

Middle Eastern (MID)

AF:

0.134

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0804

AC:

5468

AN:

67998

Other (OTH)

AF:

0.105

AC:

221

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

619

1238

1858

2477

3096

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

168

336

504

672

840

<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:

0.0862

Hom.:

1247

Bravo

AF:

0.0887

Asia WGS

AF:

0.196

AC:

683

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

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

Jan 04, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jul 10, 2011

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.

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

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

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

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 23, 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 v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.52

CADD

Benign

1.0

(source)

DANN

Benign

0.42

PhyloP100

0.49

Mutation Taster

=100/0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over