rs112315742

Variant names:

• chr12-2486117-C-T
• rs112315742
• NM_000719.7:c.771C>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.771C>T​(p.Val257Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00161 in 1,607,766 control chromosomes in the GnomAD database, including 43 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0084 (19 hom., cov: 31)
  • Exomes 𝑓: 0.00090 (24 hom.)
• Consequence: CACNA1C NM_000719.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.182

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=-0.41).
• BP6: Variant 12-2486117-C-T is Benign according to our data. Variant chr12-2486117-C-T is described in ClinVar as [Benign]. Clinvar id is 93423.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-2486117-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.182 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00839 (1277/152270) while in subpopulation AFR AF= 0.0291 (1209/41546). AF 95% confidence interval is 0.0277. There are 19 homozygotes in gnomad4. There are 614 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1277 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.771C>T	p.Val257Val	synonymous_variant	Exon 6 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.771C>T	p.Val257Val	synonymous_variant	Exon 6 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.771C>T	p.Val257Val	synonymous_variant	Exon 6 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.771C>T	p.Val257Val	synonymous_variant	Exon 6 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.861C>T	p.Val287Val	synonymous_variant	Exon 6 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.771C>T	p.Val257Val	synonymous_variant	Exon 6 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.771C>T	p.Val257Val	synonymous_variant	Exon 6 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.861C>T	p.Val287Val	synonymous_variant	Exon 6 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.771C>T	p.Val257Val	synonymous_variant	Exon 6 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.771C>T	p.Val257Val	synonymous_variant	Exon 6 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.771C>T	p.Val257Val	synonymous_variant	Exon 6 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.771C>T	p.Val257Val	synonymous_variant	Exon 6 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.861C>T	p.Val287Val	synonymous_variant	Exon 6 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.861C>T	p.Val287Val	synonymous_variant	Exon 6 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.861C>T	p.Val287Val	synonymous_variant	Exon 6 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.861C>T	p.Val287Val	synonymous_variant	Exon 6 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.771C>T	p.Val257Val	synonymous_variant	Exon 6 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.771C>T	p.Val257Val	synonymous_variant	Exon 6 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.771C>T	p.Val257Val	synonymous_variant	Exon 6 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.771C>T	p.Val257Val	synonymous_variant	Exon 6 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.771C>T	p.Val257Val	synonymous_variant	Exon 6 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.771C>T	p.Val257Val	synonymous_variant	Exon 6 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.771C>T	p.Val257Val	synonymous_variant	Exon 6 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.771C>T	p.Val257Val	synonymous_variant	Exon 6 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.771C>T	p.Val257Val	synonymous_variant	Exon 6 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.771C>T	p.Val257Val	synonymous_variant	Exon 6 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.771C>T	p.Val257Val	synonymous_variant	Exon 6 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.771C>T	p.Val257Val	synonymous_variant	Exon 6 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.771C>T	p.Val257Val	synonymous_variant	Exon 6 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.771C>T	p.Val257Val	synonymous_variant	Exon 6 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.771C>T	p.Val257Val	synonymous_variant	Exon 6 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.771C>T	p.Val257Val	synonymous_variant	Exon 6 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.771C>T	p.Val257Val	synonymous_variant	Exon 6 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.771C>T	p.Val257Val	synonymous_variant	Exon 6 of 46			ENSP00000507309.1
CACNA1C	ENST00000682152.1	c.720C>T	p.Val240Val	synonymous_variant	Exon 5 of 6			ENSP00000506759.1
CACNA1C	ENST00000480911.6	n.771C>T		non_coding_transcript_exon_variant	Exon 6 of 27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes AF: 0.00839 AC: 1276 AN: 152152 Hom.: 20 Cov.: 31

Gnomad AFR AF: 0.0292

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00321

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00574

GnomAD3 exomes AF: 0.00228 AC: 556 AN: 244228 Hom.: 8 AF XY: 0.00170 AC XY: 225 AN XY: 132206

Gnomad AFR exome AF: 0.0323

Gnomad AMR exome AF: 0.000999

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000471

Gnomad NFE exome AF: 0.0000724

Gnomad OTH exome AF: 0.00169

GnomAD4 exome AF: 0.000899 AC: 1309 AN: 1455496 Hom.: 24 Cov.: 31 AF XY: 0.000780 AC XY: 564 AN XY: 723414

Gnomad4 AFR exome AF: 0.0335

Gnomad4 AMR exome AF: 0.00126

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000118

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.0000171

Gnomad4 OTH exome AF: 0.00180

GnomAD4 genome AF: 0.00839 AC: 1277 AN: 152270 Hom.: 19 Cov.: 31 AF XY: 0.00825 AC XY: 614 AN XY: 74454

Gnomad4 AFR AF: 0.0291

Gnomad4 AMR AF: 0.00320

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.00454 Hom.: 5

Bravo AF: 0.0101

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Jul 23, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 05, 2018

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CACNA1C c.771C>T alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0029 in 271784 control chromosomes, predominantly within the African subpopulation at a frequency of 0.031, including 10 homozygotes in the gnomAD database. The observed variant frequency within African control individuals in the gnomAD database is approximately 3000 fold of the estimated maximal expected allele frequency for a pathogenic variant in CACNA1C causing Arrhythmia phenotype (1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African origin. To our knowledge, no occurrence of c.771C>T in individuals affected with Arrhythmia and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -

not provided Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Long QT syndrome Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Jul 14, 2016

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	-0.41
CADD	Benign	4.7
DANN	Benign	0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs112315742; hg19: chr12-2595283;