rs34534613

Positions:

chr12-2115283-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PP2PP3BP4_StrongBP6_Very_StrongBS1BS2

The NM_000719.7(CACNA1C):c.109G>A(p.Gly37Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00396 in 1,592,144 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.0033 ( 1 hom., cov: 34)

Exomes 𝑓: 0.0040 ( 23 hom. )

Consequence

CACNA1C
NM_000719.7 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: 9.76

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 -18 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CACNA1C. . Gene score misZ 6.4654 (greater than the threshold 3.09). Trascript score misZ 7.2674 (greater than threshold 3.09). GenCC has associacion of gene with intellectual disability, neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizures, Brugada syndrome, long QT syndrome, short QT syndrome, long qt syndrome 8, Timothy syndrome, Brugada syndrome 3.

PP3

Multiple lines of computational evidence support a deleterious effect 7: BayesDel_noAF, Cadd, Dann, phyloP100way_vertebrate, PrimateAI, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationAssessor, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.011658281).

BP6

Variant 12-2115283-G-A is Benign according to our data. Variant chr12-2115283-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 93391.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-2115283-G-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00329 (501/152364) while in subpopulation NFE AF= 0.00465 (316/68028). AF 95% confidence interval is 0.00422. There are 1 homozygotes in gnomad4. There are 241 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.

BS2

High AC in GnomAd4 at 501 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7 linkuse as main transcript	c.109G>A	p.Gly37Arg	missense_variant	2/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2 linkuse as main transcript	c.109G>A	p.Gly37Arg	missense_variant	2/47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6 linkuse as main transcript	c.109G>A	p.Gly37Arg	missense_variant	2/47	5	NM_001167623.2	ENSP00000382512		Q13936-37
CACNA1C	ENST00000399655.6 linkuse as main transcript	c.109G>A	p.Gly37Arg	missense_variant	2/47	1	NM_000719.7	ENSP00000382563		Q13936-12

Frequencies

GnomAD3 genomes

AF:

0.00329

AC:

501

AN:

152246

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000916

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00196

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000620

Gnomad FIN

AF:

0.00941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00464

Gnomad OTH

AF:

0.00382

GnomAD3 exomes

AF:

0.00346

AC:

728

AN:

210138

Hom.:

AF XY:

0.00349

AC XY:

401

AN XY:

114778

show subpopulations

Gnomad AFR exome

AF:

0.000336

Gnomad AMR exome

AF:

0.00182

Gnomad ASJ exome

AF:

0.00151

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000369

Gnomad FIN exome

AF:

0.00776

Gnomad NFE exome

AF:

0.00531

Gnomad OTH exome

AF:

0.00284

GnomAD4 exome

AF:

0.00403

AC:

5809

AN:

1439780

Hom.:

Cov.:

AF XY:

0.00399

AC XY:

2851

AN XY:

714318

show subpopulations

Gnomad4 AFR exome

AF:

0.000516

Gnomad4 AMR exome

AF:

0.00215

Gnomad4 ASJ exome

AF:

0.00124

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000384

Gnomad4 FIN exome

AF:

0.00952

Gnomad4 NFE exome

AF:

0.00452

Gnomad4 OTH exome

AF:

0.00296

GnomAD4 genome

AF:

0.00329

AC:

501

AN:

152364

Hom.:

Cov.:

AF XY:

0.00323

AC XY:

241

AN XY:

74516

show subpopulations

Gnomad4 AFR

AF:

0.000914

Gnomad4 AMR

AF:

0.00196

Gnomad4 ASJ

AF:

0.00173

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000621

Gnomad4 FIN

AF:

0.00941

Gnomad4 NFE

AF:

0.00465

Gnomad4 OTH

AF:

0.00378

Alfa

AF:

0.00392

Hom.:

Bravo

AF:

0.00251

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.00415

AC:

ESP6500AA

AF:

0.000517

AC:

ESP6500EA

AF:

0.00318

AC:

ExAC

AF:

0.00335

AC:

403

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	CACNA1C: PP2, PP3, BS1 -
Likely benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 28, 2018	This variant is associated with the following publications: (PMID: 26498160) -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 10, 2023	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:4

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 16, 2014	- -
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+	-	- -

CACNA1C-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 09, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Timothy syndrome;C2678478:Brugada syndrome 3;CN260585:Long qt syndrome 8

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 11, 2022

- -

Timothy syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Long QT syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 04, 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_addAF

Uncertain

0.15

BayesDel_noAF

Pathogenic

0.45

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.058

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

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Pathogenic

1.0

MetaRNN

Benign

0.012

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

MetaSVM

Pathogenic

1.0

MutationAssessor

Benign

1.4

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

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

PrimateAI

Pathogenic

0.86

PROVEAN

Pathogenic

-6.6

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

REVEL

Pathogenic

0.66

Sift

Pathogenic

0.0

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

Polyphen

1.0, 0.14, 1.0, 1.0

.;.;D;.;B;D;D;D;D;D;D;D;D;D;D;D;D;.;D;D;.;.;.;.

Vest4

0.76, 0.72, 0.66, 0.75, 0.72, 0.69, 0.72, 0.75, 0.73, 0.76, 0.73, 0.69, 0.74, 0.70, 0.66, 0.70, 0.65, 0.76, 0.77, 0.76, 0.70, 0.85

MutPred

0.36

.;Loss of loop (P = 0.0073);Loss of loop (P = 0.0073);Loss of loop (P = 0.0073);Loss of loop (P = 0.0073);Loss of loop (P = 0.0073);Loss of loop (P = 0.0073);Loss of loop (P = 0.0073);Loss of loop (P = 0.0073);Loss of loop (P = 0.0073);Loss of loop (P = 0.0073);Loss of loop (P = 0.0073);Loss of loop (P = 0.0073);Loss of loop (P = 0.0073);Loss of loop (P = 0.0073);Loss of loop (P = 0.0073);Loss of loop (P = 0.0073);Loss of loop (P = 0.0073);Loss of loop (P = 0.0073);Loss of loop (P = 0.0073);Loss of loop (P = 0.0073);Loss of loop (P = 0.0073);Loss of loop (P = 0.0073);Loss of loop (P = 0.0073);

MVP

0.98

MPC

2.0

ClinPred

0.035

GERP RS

5.8

gMVP

0.76

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