chr12-2679712-C-T

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.5360C>T(p.Thr1787Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000645 in 1,610,588 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T1787T) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0033 ( 2 hom., cov: 33)

Exomes 𝑓: 0.00036 ( 1 hom. )

Consequence

CACNA1C
NM_000719.7 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 2.83

Publications

8 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=0.006759852).

BP6

Variant 12-2679712-C-T is Benign according to our data. Variant chr12-2679712-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 136635.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 = 0.00335 (510/152346) while in subpopulation AFR AF = 0.0116 (483/41588). AF 95% confidence interval is 0.0108. There are 2 homozygotes in GnomAd4. There are 245 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 510 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7 link	c.5360C>T	p.Thr1787Met	missense_variant	Exon 42 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2 link	c.5360C>T	p.Thr1787Met	missense_variant	Exon 42 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CACNA1C	ENST00000399603.6 link	c.5360C>T	p.Thr1787Met	missense_variant	Exon 42 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6 link	c.5360C>T	p.Thr1787Met	missense_variant	Exon 42 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1 link	c.5594C>T	p.Thr1865Met	missense_variant	Exon 44 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8 link	c.5360C>T	p.Thr1787Met	missense_variant	Exon 42 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6 link	c.5327C>T	p.Thr1776Met	missense_variant	Exon 41 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1 link	c.5525C>T	p.Thr1842Met	missense_variant	Exon 43 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9 link	c.5504C>T	p.Thr1835Met	missense_variant	Exon 44 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7 link	c.5483C>T	p.Thr1828Met	missense_variant	Exon 42 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12 link	c.5360C>T	p.Thr1787Met	missense_variant	Exon 42 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6 link	c.5360C>T	p.Thr1787Met	missense_variant	Exon 42 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1 link	c.5450C>T	p.Thr1817Met	missense_variant	Exon 42 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1 link	c.5450C>T	p.Thr1817Met	missense_variant	Exon 42 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1 link	c.5450C>T	p.Thr1817Met	missense_variant	Exon 42 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1 link	c.5450C>T	p.Thr1817Met	missense_variant	Exon 42 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5 link	c.5444C>T	p.Thr1815Met	missense_variant	Exon 43 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10 link	c.5435C>T	p.Thr1812Met	missense_variant	Exon 43 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5 link	c.5420C>T	p.Thr1807Met	missense_variant	Exon 43 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5 link	c.5417C>T	p.Thr1806Met	missense_variant	Exon 42 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5 link	c.5417C>T	p.Thr1806Met	missense_variant	Exon 42 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7 link	c.5417C>T	p.Thr1806Met	missense_variant	Exon 42 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5 link	c.5411C>T	p.Thr1804Met	missense_variant	Exon 42 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1 link	c.5402C>T	p.Thr1801Met	missense_variant	Exon 42 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5 link	c.5384C>T	p.Thr1795Met	missense_variant	Exon 41 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5 link	c.5384C>T	p.Thr1795Met	missense_variant	Exon 41 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5 link	c.5378C>T	p.Thr1793Met	missense_variant	Exon 41 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5 link	c.5360C>T	p.Thr1787Met	missense_variant	Exon 42 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5 link	c.5360C>T	p.Thr1787Met	missense_variant	Exon 42 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6 link	c.5360C>T	p.Thr1787Met	missense_variant	Exon 42 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5 link	c.5360C>T	p.Thr1787Met	missense_variant	Exon 42 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1 link	c.5360C>T	p.Thr1787Met	missense_variant	Exon 42 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1 link	c.5351C>T	p.Thr1784Met	missense_variant	Exon 42 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1 link	c.5327C>T	p.Thr1776Met	missense_variant	Exon 41 of 46			ENSP00000507309.1

Frequencies

GnomAD3 genomes

AF:

0.00334

AC:

508

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0116

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00111

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.000916

AC:

219

AN:

239144

AF XY:

0.000707

show subpopulations

Gnomad AFR exome

AF:

0.0131

Gnomad AMR exome

AF:

0.000828

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000561

Gnomad OTH exome

AF:

0.000339

GnomAD4 exome

AF:

0.000363

AC:

529

AN:

1458242

Hom.:

Cov.:

AF XY:

0.000316

AC XY:

229

AN XY:

725132

show subpopulations

African (AFR)

AF:

0.0109

AC:

362

AN:

33352

American (AMR)

AF:

0.000882

AC:

AN:

44238

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25990

East Asian (EAS)

AF:

0.00

AC:

AN:

39572

South Asian (SAS)

AF:

0.0000584

AC:

AN:

85662

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53048

Middle Eastern (MID)

AF:

0.00121

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0000576

AC:

AN:

1110378

Other (OTH)

AF:

0.000863

AC:

AN:

60238

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

130

163

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.00335

AC:

510

AN:

152346

Hom.:

Cov.:

AF XY:

0.00329

AC XY:

245

AN XY:

74490

show subpopulations

African (AFR)

AF:

0.0116

AC:

483

AN:

41588

American (AMR)

AF:

0.00105

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.000207

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

68026

Other (OTH)

AF:

0.00142

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

102

127

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:

0.00172

Hom.:

Bravo

AF:

0.00365

ESP6500AA

AF:

0.0106

AC:

ESP6500EA

AF:

0.000239

AC:

ExAC

AF:

0.00116

AC:

140

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Oct 07, 2013

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.

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

not provided

Benign:2

Sep 07, 2016

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: The CACNA1C c.5360C>T (p.Thr1787Met) variant involves the alteration of a conserved nucleotide. 3/5 in silico tools predict a benign outcome for this variant. This variant was found in 126/107256 control chromosomes (one homozygote), predominantly observed in the African subpopulation at a frequency of 0.0161245 (115/7132). This frequency is about 1612 times the estimated maximal expected allele frequency of a pathogenic CACNA1C variant (0.00001), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. This variant has been reported in three patients with arrhythmia in literature (Burashnikov_2010, Steffensen_2015, Wemhoner_2015), however without evidence for pathogenicity. One of the patients also carried a truncating variant in other gene, AKAP9 p.Thr3473AsnfsX3. Multiple clinical diagnostic laboratories have classified this variant as benign. Taken together, this variant is classified as Benign.

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Brugada syndrome

Benign:1

Dec 24, 2018

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Long QT syndrome

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Cardiovascular phenotype

Benign:1

Jul 11, 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

AlphaMissense

Benign

0.096

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.15

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.012

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

Eigen

Benign

-0.12

Eigen_PC

Benign

-0.23

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.0

.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.

MetaRNN

Benign

0.0068

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

MetaSVM

Uncertain

0.27

MutationAssessor

Benign

0.0

.;.;.;.;.;.;.;.;.;.;L;.;.;.;.;.;.;.;.;.;.;.;.

PhyloP100

2.8

PrimateAI

Benign

0.39

PROVEAN

Benign

-1.5

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

REVEL

Uncertain

0.34

Sift

Benign

0.050

D;T;T;D;T;T;D;D;D;D;T;T;T;D;T;D;D;D;D;D;T;D;.

Sift4G

Benign

0.10

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

Vest4

0.23

ClinPred

0.013

GERP RS

1.8

gMVP

0.39

Mutation Taster

=100/0

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