rs113595214

Variant names:

• chr12-2679449-C-T
• rs113595214
• NM_000719.7:c.5097C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_000719.7(CACNA1C):​c.5097C>T​(p.Ala1699Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00798 in 1,556,730 control chromosomes in the GnomAD database, including 65 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0069 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0081 (60 hom.)
• Consequence: CACNA1C NM_000719.7 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.137
• Publications: 5 publications found

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]

ITFG2-AS1 (HGNC:53128): (ITFG2 antisense RNA 1)

CACNA1C-AS1 (HGNC:40119): (CACNA1C antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BP6: Variant 12-2679449-C-T is Benign according to our data. Variant chr12-2679449-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 93409.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.137 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00688 (1045/151934) while in subpopulation NFE AF = 0.0108 (731/67942). AF 95% confidence interval is 0.0101. There are 5 homozygotes in GnomAd4. There are 480 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1045 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.5097C>T	p.Ala1699Ala	synonymous_variant	Exon 42 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.5097C>T	p.Ala1699Ala	synonymous_variant	Exon 42 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.5097C>T	p.Ala1699Ala	synonymous_variant	Exon 42 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.5097C>T	p.Ala1699Ala	synonymous_variant	Exon 42 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.5331C>T	p.Ala1777Ala	synonymous_variant	Exon 44 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.5097C>T	p.Ala1699Ala	synonymous_variant	Exon 42 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.5064C>T	p.Ala1688Ala	synonymous_variant	Exon 41 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.5262C>T	p.Ala1754Ala	synonymous_variant	Exon 43 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.5241C>T	p.Ala1747Ala	synonymous_variant	Exon 44 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.5220C>T	p.Ala1740Ala	synonymous_variant	Exon 42 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.5097C>T	p.Ala1699Ala	synonymous_variant	Exon 42 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.5097C>T	p.Ala1699Ala	synonymous_variant	Exon 42 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.5187C>T	p.Ala1729Ala	synonymous_variant	Exon 42 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.5187C>T	p.Ala1729Ala	synonymous_variant	Exon 42 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.5187C>T	p.Ala1729Ala	synonymous_variant	Exon 42 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.5187C>T	p.Ala1729Ala	synonymous_variant	Exon 42 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.5181C>T	p.Ala1727Ala	synonymous_variant	Exon 43 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.5172C>T	p.Ala1724Ala	synonymous_variant	Exon 43 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.5157C>T	p.Ala1719Ala	synonymous_variant	Exon 43 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.5154C>T	p.Ala1718Ala	synonymous_variant	Exon 42 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.5154C>T	p.Ala1718Ala	synonymous_variant	Exon 42 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.5154C>T	p.Ala1718Ala	synonymous_variant	Exon 42 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.5148C>T	p.Ala1716Ala	synonymous_variant	Exon 42 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.5139C>T	p.Ala1713Ala	synonymous_variant	Exon 42 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.5121C>T	p.Ala1707Ala	synonymous_variant	Exon 41 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.5121C>T	p.Ala1707Ala	synonymous_variant	Exon 41 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.5115C>T	p.Ala1705Ala	synonymous_variant	Exon 41 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.5097C>T	p.Ala1699Ala	synonymous_variant	Exon 42 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.5097C>T	p.Ala1699Ala	synonymous_variant	Exon 42 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.5097C>T	p.Ala1699Ala	synonymous_variant	Exon 42 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.5097C>T	p.Ala1699Ala	synonymous_variant	Exon 42 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.5097C>T	p.Ala1699Ala	synonymous_variant	Exon 42 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.5088C>T	p.Ala1696Ala	synonymous_variant	Exon 42 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.5064C>T	p.Ala1688Ala	synonymous_variant	Exon 41 of 46			ENSP00000507309.1

Frequencies

GnomAD3 genomes AF: 0.00688 AC: 1044 AN: 151812 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.00160

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00518

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00105

Gnomad FIN AF: 0.0115

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0108

Gnomad OTH AF: 0.0129

GnomAD2 exomes AF: 0.00699 AC: 1293 AN: 184942 AF XY: 0.00684

Gnomad AFR exome AF: 0.00122

Gnomad AMR exome AF: 0.00562

Gnomad ASJ exome AF: 0.00426

Gnomad EAS exome AF: 0.0000665

Gnomad FIN exome AF: 0.0142

Gnomad NFE exome AF: 0.00947

Gnomad OTH exome AF: 0.0117

GnomAD4 exome AF: 0.00810 AC: 11383 AN: 1404796 Hom.: 60 Cov.: 31 AF XY: 0.00801 AC XY: 5542 AN XY: 692098

African (AFR) AF: 0.00198 AC: 64 AN: 32322

American (AMR) AF: 0.00580 AC: 230 AN: 39634

Ashkenazi Jewish (ASJ) AF: 0.00303 AC: 70 AN: 23068

East Asian (EAS) AF: 0.0000526 AC: 2 AN: 38008

South Asian (SAS) AF: 0.00144 AC: 110 AN: 76278

European-Finnish (FIN) AF: 0.0147 AC: 732 AN: 49692

Middle Eastern (MID) AF: 0.0230 AC: 128 AN: 5562

European-Non Finnish (NFE) AF: 0.00884 AC: 9561 AN: 1082130

Other (OTH) AF: 0.00836 AC: 486 AN: 58102

GnomAD4 genome AF: 0.00688 AC: 1045 AN: 151934 Hom.: 5 Cov.: 33 AF XY: 0.00646 AC XY: 480 AN XY: 74256

African (AFR) AF: 0.00162 AC: 67 AN: 41484

American (AMR) AF: 0.00518 AC: 79 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 9 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5102

South Asian (SAS) AF: 0.00105 AC: 5 AN: 4742

European-Finnish (FIN) AF: 0.0115 AC: 122 AN: 10608

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0108 AC: 731 AN: 67942

Other (OTH) AF: 0.0128 AC: 27 AN: 2116

Alfa AF: 0.00952 Hom.: 3

Bravo AF: 0.00588

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Jul 10, 2011

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Dec 17, 2012

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:3

Oct 13, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CACNA1C: BP4, BP7, BS2 -

Timothy syndrome;C2678478:Brugada syndrome 3;CN260585:Long qt syndrome 8 Benign:1

Jul 26, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Long QT syndrome Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

May 18, 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	-0.31
CADD	Benign	11
DANN	Benign	0.84
PhyloP100		0.14
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

dbSNP: rs113595214; hg19: chr12-2788615; COSMIC: COSV59760942; COSMIC: COSV59760942;