rs34534613

chr12-2115283-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PP2 PP3 BP4_Strong BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 9.76

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]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• PP2: Missense variant where missense usually causes diseases, CACNA1C
• 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 GnomAd at 501 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1C	NM_000719.7	c.109G>A	p.Gly37Arg	missense_variant	2/47	ENST00000399655.6
CACNA1C	NM_001167623.2	c.109G>A	p.Gly37Arg	missense_variant	2/47	ENST00000399603.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1C	ENST00000399603.6	c.109G>A	p.Gly37Arg	missense_variant	2/47	5	NM_001167623.2
CACNA1C	ENST00000399655.6	c.109G>A	p.Gly37Arg	missense_variant	2/47	1	NM_000719.7

Frequencies

GnomAD3 genomes AF: 0.00329 AC: 501 AN: 152246 Hom.: 1 Cov.: 34

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.: 2 AF XY: 0.00349 AC XY: 401 AN XY: 114778

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.: 23 Cov.: 32 AF XY: 0.00399 AC XY: 2851 AN XY: 714318

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.: 1 Cov.: 34 AF XY: 0.00323 AC XY: 241 AN XY: 74516

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.: 3

Bravo AF: 0.00251

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00415 AC: 16

ESP6500AA AF: 0.000517 AC: 2

ESP6500EA AF: 0.00318 AC: 26

ExAC AF: 0.00335 AC: 403

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 16, 2014	- -

not provided Benign:4

Likely benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
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	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	CACNA1C: PP2, PP3, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 28, 2018	This variant is associated with the following publications: (PMID: 26498160) -

CACNA1C-related disorder Benign:1

Likely benign, criteria provided, single submitter

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

Invitae

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	D
BayesDel_noAF	Pathogenic	0.45
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	1.0	D
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	D
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	D
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	T
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

Other links and lift over

dbSNP: rs34534613; hg19: chr12-2224449;