12-2607008-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_ModerateBP6BP7BS1BS2

The NM_000719.7(CACNA1C):c.3234C>T(p.Asp1078Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00096 in 1,613,952 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00079 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00098 ( 4 hom. )

Consequence

CACNA1C
NM_000719.7 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:10

Conservation

PhyloP100: -2.29

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 links:

CACNA1C-AS3 (HGNC:40117): (CACNA1C antisense RNA 3)

CACNA1C-AS3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.34).

BP6

Variant 12-2607008-C-T is Benign according to our data. Variant chr12-2607008-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 195932.

BP7

Synonymous conserved (PhyloP=-2.29 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000795 (121/152288) while in subpopulation NFE AF = 0.00138 (94/68024). AF 95% confidence interval is 0.00116. There are 0 homozygotes in GnomAd4. There are 57 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 121 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7 link	c.3234C>T	p.Asp1078Asp	synonymous_variant	Exon 26 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2 link	c.3234C>T	p.Asp1078Asp	synonymous_variant	Exon 26 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CACNA1C	ENST00000399603.6 link	c.3234C>T	p.Asp1078Asp	synonymous_variant	Exon 26 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6 link	c.3234C>T	p.Asp1078Asp	synonymous_variant	Exon 26 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1 link	c.3384C>T	p.Asp1128Asp	synonymous_variant	Exon 27 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8 link	c.3234C>T	p.Asp1078Asp	synonymous_variant	Exon 26 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6 link	c.3234C>T	p.Asp1078Asp	synonymous_variant	Exon 26 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1 link	c.3399C>T	p.Asp1133Asp	synonymous_variant	Exon 27 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9 link	c.3294C>T	p.Asp1098Asp	synonymous_variant	Exon 27 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7 link	c.3234C>T	p.Asp1078Asp	synonymous_variant	Exon 26 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12 link	c.3234C>T	p.Asp1078Asp	synonymous_variant	Exon 26 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6 link	c.3234C>T	p.Asp1078Asp	synonymous_variant	Exon 26 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1 link	c.3324C>T	p.Asp1108Asp	synonymous_variant	Exon 26 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1 link	c.3324C>T	p.Asp1108Asp	synonymous_variant	Exon 26 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1 link	c.3324C>T	p.Asp1108Asp	synonymous_variant	Exon 26 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1 link	c.3324C>T	p.Asp1108Asp	synonymous_variant	Exon 26 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5 link	c.3234C>T	p.Asp1078Asp	synonymous_variant	Exon 26 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10 link	c.3309C>T	p.Asp1103Asp	synonymous_variant	Exon 27 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5 link	c.3294C>T	p.Asp1098Asp	synonymous_variant	Exon 27 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5 link	c.3234C>T	p.Asp1078Asp	synonymous_variant	Exon 26 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5 link	c.3234C>T	p.Asp1078Asp	synonymous_variant	Exon 26 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7 link	c.3234C>T	p.Asp1078Asp	synonymous_variant	Exon 26 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5 link	c.3234C>T	p.Asp1078Asp	synonymous_variant	Exon 26 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1 link	c.3309C>T	p.Asp1103Asp	synonymous_variant	Exon 27 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5 link	c.3234C>T	p.Asp1078Asp	synonymous_variant	Exon 26 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5 link	c.3234C>T	p.Asp1078Asp	synonymous_variant	Exon 26 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5 link	c.3234C>T	p.Asp1078Asp	synonymous_variant	Exon 26 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5 link	c.3234C>T	p.Asp1078Asp	synonymous_variant	Exon 26 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5 link	c.3234C>T	p.Asp1078Asp	synonymous_variant	Exon 26 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6 link	c.3234C>T	p.Asp1078Asp	synonymous_variant	Exon 26 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5 link	c.3234C>T	p.Asp1078Asp	synonymous_variant	Exon 26 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1 link	c.3234C>T	p.Asp1078Asp	synonymous_variant	Exon 26 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1 link	c.3225C>T	p.Asp1075Asp	synonymous_variant	Exon 26 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1 link	c.3234C>T	p.Asp1078Asp	synonymous_variant	Exon 26 of 46			ENSP00000507309.1
CACNA1C	ENST00000480911.6 link	n.*1841C>T		non_coding_transcript_exon_variant	Exon 24 of 27	5		ENSP00000437936.2
CACNA1C	ENST00000480911.6 link	n.*1841C>T		3_prime_UTR_variant	Exon 24 of 27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes

AF:

0.000795

AC:

121

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00432

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00138

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000867

AC:

216

AN:

249226

AF XY:

0.000865

show subpopulations

Gnomad AFR exome

AF:

0.0000646

Gnomad AMR exome

AF:

0.000203

Gnomad ASJ exome

AF:

0.00397

Gnomad EAS exome

AF:

0.000111

Gnomad FIN exome

AF:

0.000650

Gnomad NFE exome

AF:

0.00127

Gnomad OTH exome

AF:

0.000991

GnomAD4 exome

AF:

0.000978

AC:

1429

AN:

1461664

Hom.:

Cov.:

AF XY:

0.00102

AC XY:

745

AN XY:

727120

show subpopulations

African (AFR)

AF:

0.0000896

AC:

AN:

33480

American (AMR)

AF:

0.000201

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00325

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.000487

AC:

AN:

53402

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00112

AC:

1244

AN:

1111830

Other (OTH)

AF:

0.000944

AC:

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

146

218

291

364

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

128

160

<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:

0.000795

AC:

121

AN:

152288

Hom.:

Cov.:

AF XY:

0.000765

AC XY:

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41562

American (AMR)

AF:

0.000327

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00432

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5178

South Asian (SAS)

AF:

0.000208

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.000377

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00138

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

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:

0.00125

Hom.:

Bravo

AF:

0.000752

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00136

EpiControl

AF:

0.000889

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:10

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:5

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance:Likely 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

Mar 25, 2021

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

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

Uncertain:1Benign:2

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CACNA1C: BP4, BP7

Sep 29, 2015

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Timothy syndrome;C2678478:Brugada syndrome 3;C5774213:Neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizures;CN260585:Long QT syndrome 8

Benign:1

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant has not been reported in the literature but is present in the Genome Aggregation Database (Highest reported MAF: 0.4% [41/10356] including 2 total homozygotes; https://gnomad.broadinstitute.org/variant/12-2716174-C-T?dataset=gnomad_r2_1). This variant is present in ClinVar (Variation ID:195932). Of note, this variant is a silent variant and does not change the amino acid, is not predicted to impact splicing, and this nucleotide position is poorly conserved evolutionarily, reducing the probability that this variant is disease-causing. In summary, data on this variant suggests that this variant does not cause disease but requires further evidence. Therefore, this variant is classified as likely benign.

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

May 18, 2015

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

-0.34

CADD

Benign

4.1

(source)

DANN

Benign

0.82

PhyloP100

-2.3

Mutation Taster

=93/7

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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