rs34419050

chr12-2115345-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_000719.7(CACNA1C):c.171C>T(p.Asp57=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0229 in 1,588,598 control chromosomes in the GnomAD database, including 524 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (28 hom., cov: 34)
  • Exomes 𝑓: 0.024 (496 hom.)
• Consequence: CACNA1C NM_000719.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.301

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 12-2115345-C-T is Benign according to our data. Variant chr12-2115345-C-T is described in ClinVar as [Benign]. Clinvar id is 35767.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-2115345-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.301 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0164 (2505/152362) while in subpopulation SAS AF= 0.0379 (183/4832). AF 95% confidence interval is 0.0334. There are 28 homozygotes in gnomad4. There are 1210 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 2506 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1C	NM_000719.7	c.171C>T	p.Asp57=	synonymous_variant	2/47	ENST00000399655.6
CACNA1C	NM_001167623.2	c.171C>T	p.Asp57=	synonymous_variant	2/47	ENST00000399603.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1C	ENST00000399603.6	c.171C>T	p.Asp57=	synonymous_variant	2/47	5	NM_001167623.2
CACNA1C	ENST00000399655.6	c.171C>T	p.Asp57=	synonymous_variant	2/47	1	NM_000719.7

Frequencies

GnomAD3 genomes AF: 0.0165 AC: 2506 AN: 152244 Hom.: 28 Cov.: 34

Gnomad AFR AF: 0.00417

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0113

Gnomad ASJ AF: 0.0141

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0380

Gnomad FIN AF: 0.0135

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0256

Gnomad OTH AF: 0.0153

GnomAD3 exomes AF: 0.0205 AC: 4122 AN: 201186 Hom.: 68 AF XY: 0.0224 AC XY: 2481 AN XY: 110836

Gnomad AFR exome AF: 0.00325

Gnomad AMR exome AF: 0.00892

Gnomad ASJ exome AF: 0.0193

Gnomad EAS exome AF: 0.000139

Gnomad SAS exome AF: 0.0371

Gnomad FIN exome AF: 0.0116

Gnomad NFE exome AF: 0.0265

Gnomad OTH exome AF: 0.0173

GnomAD4 exome AF: 0.0236 AC: 33845 AN: 1436236 Hom.: 496 Cov.: 32 AF XY: 0.0244 AC XY: 17395 AN XY: 713112

Gnomad4 AFR exome AF: 0.00320

Gnomad4 AMR exome AF: 0.00909

Gnomad4 ASJ exome AF: 0.0190

Gnomad4 EAS exome AF: 0.000132

Gnomad4 SAS exome AF: 0.0390

Gnomad4 FIN exome AF: 0.0114

Gnomad4 NFE exome AF: 0.0252

Gnomad4 OTH exome AF: 0.0196

GnomAD4 genome AF: 0.0164 AC: 2505 AN: 152362 Hom.: 28 Cov.: 34 AF XY: 0.0162 AC XY: 1210 AN XY: 74514

Gnomad4 AFR AF: 0.00418

Gnomad4 AMR AF: 0.0114

Gnomad4 ASJ AF: 0.0141

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0379

Gnomad4 FIN AF: 0.0135

Gnomad4 NFE AF: 0.0256

Gnomad4 OTH AF: 0.0151

Alfa AF: 0.0210 Hom.: 5

Bravo AF: 0.0149

Asia WGS AF: 0.0110 AC: 38 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

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, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 03, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 03, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Long QT syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 25, 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. -

Cardiac arrhythmia Benign:1

Benign, no assertion criteria provided

clinical testing

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

Apr 22, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
Cadd	Benign	5.6
Dann	Benign	0.78

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: rs34419050; hg19: chr12-2224511;