rs113869350

Variant names:

• chr12-2115387-G-A
• rs113869350
• NM_000719.7:c.213G>A

Your query was ambiguous. Multiple possible variants found:

• chr12-2115387-G-A
• chr12-2115387-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000719.7(CACNA1C):​c.213G>A​(p.Ala71Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00282 in 1,609,788 control chromosomes in the GnomAD database, including 89 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (52 hom., cov: 34)
  • Exomes 𝑓: 0.0018 (37 hom.)
• Consequence: CACNA1C NM_000719.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -3.40

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 12-2115387-G-A is Benign according to our data. Variant chr12-2115387-G-A is described in ClinVar as [Benign]. Clinvar id is 238171.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-2115387-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-3.4 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.013 (1979/152336) while in subpopulation AFR AF= 0.0444 (1848/41576). AF 95% confidence interval is 0.0428. There are 52 homozygotes in gnomad4. There are 947 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1979 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.213G>A	p.Ala71Ala	synonymous_variant	Exon 2 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.213G>A	p.Ala71Ala	synonymous_variant	Exon 2 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.213G>A	p.Ala71Ala	synonymous_variant	Exon 2 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.213G>A	p.Ala71Ala	synonymous_variant	Exon 2 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.303G>A	p.Ala101Ala	synonymous_variant	Exon 2 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.213G>A	p.Ala71Ala	synonymous_variant	Exon 2 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.213G>A	p.Ala71Ala	synonymous_variant	Exon 2 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.303G>A	p.Ala101Ala	synonymous_variant	Exon 2 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.213G>A	p.Ala71Ala	synonymous_variant	Exon 2 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.213G>A	p.Ala71Ala	synonymous_variant	Exon 2 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.213G>A	p.Ala71Ala	synonymous_variant	Exon 2 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.213G>A	p.Ala71Ala	synonymous_variant	Exon 2 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.303G>A	p.Ala101Ala	synonymous_variant	Exon 2 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.303G>A	p.Ala101Ala	synonymous_variant	Exon 2 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.303G>A	p.Ala101Ala	synonymous_variant	Exon 2 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.303G>A	p.Ala101Ala	synonymous_variant	Exon 2 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.213G>A	p.Ala71Ala	synonymous_variant	Exon 2 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.213G>A	p.Ala71Ala	synonymous_variant	Exon 2 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.213G>A	p.Ala71Ala	synonymous_variant	Exon 2 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.213G>A	p.Ala71Ala	synonymous_variant	Exon 2 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.213G>A	p.Ala71Ala	synonymous_variant	Exon 2 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.213G>A	p.Ala71Ala	synonymous_variant	Exon 2 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.213G>A	p.Ala71Ala	synonymous_variant	Exon 2 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.213G>A	p.Ala71Ala	synonymous_variant	Exon 2 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.213G>A	p.Ala71Ala	synonymous_variant	Exon 2 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.213G>A	p.Ala71Ala	synonymous_variant	Exon 2 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.213G>A	p.Ala71Ala	synonymous_variant	Exon 2 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.213G>A	p.Ala71Ala	synonymous_variant	Exon 2 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.213G>A	p.Ala71Ala	synonymous_variant	Exon 2 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.213G>A	p.Ala71Ala	synonymous_variant	Exon 2 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.213G>A	p.Ala71Ala	synonymous_variant	Exon 2 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.213G>A	p.Ala71Ala	synonymous_variant	Exon 2 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.213G>A	p.Ala71Ala	synonymous_variant	Exon 2 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.213G>A	p.Ala71Ala	synonymous_variant	Exon 2 of 46			ENSP00000507309.1
CACNA1C	ENST00000682152.1	c.162G>A	p.Ala54Ala	synonymous_variant	Exon 1 of 6			ENSP00000506759.1
CACNA1C	ENST00000480911.6	n.213G>A		non_coding_transcript_exon_variant	Exon 2 of 27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes AF: 0.0129 AC: 1969 AN: 152218 Hom.: 51 Cov.: 34

Gnomad AFR AF: 0.0444

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00451

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.00812

GnomAD3 exomes AF: 0.00329 AC: 792 AN: 240666 Hom.: 17 AF XY: 0.00243 AC XY: 319 AN XY: 131530

Gnomad AFR exome AF: 0.0422

Gnomad AMR exome AF: 0.00254

Gnomad ASJ exome AF: 0.00294

Gnomad EAS exome AF: 0.0000568

Gnomad SAS exome AF: 0.000200

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000494

Gnomad OTH exome AF: 0.00239

GnomAD4 exome AF: 0.00176 AC: 2559 AN: 1457452 Hom.: 37 Cov.: 32 AF XY: 0.00153 AC XY: 1111 AN XY: 724948

Gnomad4 AFR exome AF: 0.0450

Gnomad4 AMR exome AF: 0.00275

Gnomad4 ASJ exome AF: 0.00357

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.000222

Gnomad4 FIN exome AF: 0.0000195

Gnomad4 NFE exome AF: 0.000476

Gnomad4 OTH exome AF: 0.00438

GnomAD4 genome AF: 0.0130 AC: 1979 AN: 152336 Hom.: 52 Cov.: 34 AF XY: 0.0127 AC XY: 947 AN XY: 74474

Gnomad4 AFR AF: 0.0444

Gnomad4 AMR AF: 0.00451

Gnomad4 ASJ AF: 0.00375

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000382

Gnomad4 OTH AF: 0.00992

Alfa AF: 0.00432 Hom.: 3

Bravo AF: 0.0146

Asia WGS AF: 0.00635 AC: 22 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Aug 23, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2016

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 03, 2015

GeneDx

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

Jul 28, 2015

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	-0.86
CADD	Benign	1.3
DANN	Benign	0.60

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: rs113869350; hg19: chr12-2224553; COSMIC: COSV104405042; COSMIC: COSV104405042;