rs41276710

Positions:

chr12-2665667-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000719.7(CACNA1C):c.4485T>C(p.Asp1495=) 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:7

Conservation

PhyloP100: 0.470

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 93407.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-2665667-T-C is described in Lovd as [Benign].

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/exons	MANE	UniProt
CACNA1C	NM_000719.7 linkuse as main transcript	c.4485T>C	p.Asp1495=	synonymous_variant	36/47	ENST00000399655.6
CACNA1C	NM_001167623.2 linkuse as main transcript	c.4485T>C	p.Asp1495=	synonymous_variant	36/47	ENST00000399603.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1C	ENST00000399603.6 linkuse as main transcript	c.4485T>C	p.Asp1495=	synonymous_variant	36/47	5	NM_001167623.2		Q13936-37
CACNA1C	ENST00000399655.6 linkuse as main transcript	c.4485T>C	p.Asp1495=	synonymous_variant	36/47	1	NM_000719.7		Q13936-12

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

GnomAD3 exomes

AF:

0.0122

AC:

3039

AN:

249384

Hom.:

123

AF XY:

0.0102

AC XY:

1385

AN XY:

135292

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 SAS exome

AF:

0.00729

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

Gnomad4 AFR exome

AF:

0.141

Gnomad4 AMR exome

AF:

0.00897

Gnomad4 ASJ exome

AF:

0.00149

Gnomad4 EAS exome

AF:

0.000252

Gnomad4 SAS exome

AF:

0.00820

Gnomad4 FIN exome

AF:

0.000206

Gnomad4 NFE exome

AF:

0.00284

Gnomad4 OTH exome

AF:

0.0116

GnomAD4 genome

AF:

0.0391

AC:

5953

AN:

152210

Hom.:

350

Cov.:

AF XY:

0.0378

AC XY:

2813

AN XY:

74432

show subpopulations

Gnomad4 AFR

AF:

0.129

Gnomad4 AMR

AF:

0.0148

Gnomad4 ASJ

AF:

0.00230

Gnomad4 EAS

AF:

0.000580

Gnomad4 SAS

AF:

0.00996

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.00348

Gnomad4 OTH

AF:

0.0289

Alfa

AF:

0.0169

Hom.:

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:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 23, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Long QT syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 26, 2015

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

DANN

Benign

0.84

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over