rs1051375

Variant names:

• chr12-2679713-G-A
• rs1051375
• NM_000719.7:c.5361G>A

Your query was ambiguous. Multiple possible variants found:

• chr12-2679713-G-A
• chr12-2679713-G-C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000719.7(CACNA1C):​c.5361G>A​(p.Thr1787Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.694 in 1,608,514 control chromosomes in the GnomAD database, including 398,256 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.58 (28886 hom., cov: 34)
  • Exomes 𝑓: 0.71 (369370 hom.)
• Consequence: CACNA1C NM_000719.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -3.82
• Publications: 43 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 12-2679713-G-A is Benign according to our data. Variant chr12-2679713-G-A is described in ClinVar as Benign. ClinVar VariationId is 93413.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.82 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.721 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.5361G>A	p.Thr1787Thr	synonymous_variant	Exon 42 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.5361G>A	p.Thr1787Thr	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.5361G>A	p.Thr1787Thr	synonymous_variant	Exon 42 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.5361G>A	p.Thr1787Thr	synonymous_variant	Exon 42 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.5595G>A	p.Thr1865Thr	synonymous_variant	Exon 44 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.5361G>A	p.Thr1787Thr	synonymous_variant	Exon 42 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.5328G>A	p.Thr1776Thr	synonymous_variant	Exon 41 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.5526G>A	p.Thr1842Thr	synonymous_variant	Exon 43 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.5505G>A	p.Thr1835Thr	synonymous_variant	Exon 44 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.5484G>A	p.Thr1828Thr	synonymous_variant	Exon 42 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.5361G>A	p.Thr1787Thr	synonymous_variant	Exon 42 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.5361G>A	p.Thr1787Thr	synonymous_variant	Exon 42 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.5451G>A	p.Thr1817Thr	synonymous_variant	Exon 42 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.5451G>A	p.Thr1817Thr	synonymous_variant	Exon 42 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.5451G>A	p.Thr1817Thr	synonymous_variant	Exon 42 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.5451G>A	p.Thr1817Thr	synonymous_variant	Exon 42 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.5445G>A	p.Thr1815Thr	synonymous_variant	Exon 43 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.5436G>A	p.Thr1812Thr	synonymous_variant	Exon 43 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.5421G>A	p.Thr1807Thr	synonymous_variant	Exon 43 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.5418G>A	p.Thr1806Thr	synonymous_variant	Exon 42 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.5418G>A	p.Thr1806Thr	synonymous_variant	Exon 42 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.5418G>A	p.Thr1806Thr	synonymous_variant	Exon 42 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.5412G>A	p.Thr1804Thr	synonymous_variant	Exon 42 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.5403G>A	p.Thr1801Thr	synonymous_variant	Exon 42 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.5385G>A	p.Thr1795Thr	synonymous_variant	Exon 41 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.5385G>A	p.Thr1795Thr	synonymous_variant	Exon 41 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.5379G>A	p.Thr1793Thr	synonymous_variant	Exon 41 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.5361G>A	p.Thr1787Thr	synonymous_variant	Exon 42 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.5361G>A	p.Thr1787Thr	synonymous_variant	Exon 42 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.5361G>A	p.Thr1787Thr	synonymous_variant	Exon 42 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.5361G>A	p.Thr1787Thr	synonymous_variant	Exon 42 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.5361G>A	p.Thr1787Thr	synonymous_variant	Exon 42 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.5352G>A	p.Thr1784Thr	synonymous_variant	Exon 42 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.5328G>A	p.Thr1776Thr	synonymous_variant	Exon 41 of 46			ENSP00000507309.1

Frequencies

GnomAD3 genomes AF: 0.578 AC: 87834 AN: 152028 Hom.: 28877 Cov.: 34

Gnomad AFR AF: 0.236

Gnomad AMI AF: 0.613

Gnomad AMR AF: 0.644

Gnomad ASJ AF: 0.672

Gnomad EAS AF: 0.624

Gnomad SAS AF: 0.667

Gnomad FIN AF: 0.767

Gnomad MID AF: 0.462

Gnomad NFE AF: 0.726

Gnomad OTH AF: 0.586

GnomAD2 exomes AF: 0.677 AC: 160515 AN: 236924 AF XY: 0.683

Gnomad AFR exome AF: 0.236

Gnomad AMR exome AF: 0.706

Gnomad ASJ exome AF: 0.664

Gnomad EAS exome AF: 0.624

Gnomad FIN exome AF: 0.763

Gnomad NFE exome AF: 0.723

Gnomad OTH exome AF: 0.676

GnomAD4 exome AF: 0.706 AC: 1028616 AN: 1456368 Hom.: 369370 Cov.: 61 AF XY: 0.706 AC XY: 511204 AN XY: 724000

African (AFR) AF: 0.211 AC: 7042 AN: 33324

American (AMR) AF: 0.696 AC: 30584 AN: 43920

Ashkenazi Jewish (ASJ) AF: 0.661 AC: 17162 AN: 25966

East Asian (EAS) AF: 0.598 AC: 23611 AN: 39470

South Asian (SAS) AF: 0.657 AC: 56201 AN: 85508

European-Finnish (FIN) AF: 0.758 AC: 40148 AN: 52972

Middle Eastern (MID) AF: 0.511 AC: 2946 AN: 5762

European-Non Finnish (NFE) AF: 0.731 AC: 810544 AN: 1109268

Other (OTH) AF: 0.671 AC: 40378 AN: 60178

GnomAD4 genome AF: 0.577 AC: 87853 AN: 152146 Hom.: 28886 Cov.: 34 AF XY: 0.581 AC XY: 43218 AN XY: 74394

African (AFR) AF: 0.236 AC: 9782 AN: 41508

American (AMR) AF: 0.644 AC: 9847 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.672 AC: 2333 AN: 3470

East Asian (EAS) AF: 0.623 AC: 3211 AN: 5152

South Asian (SAS) AF: 0.666 AC: 3212 AN: 4824

European-Finnish (FIN) AF: 0.767 AC: 8132 AN: 10602

Middle Eastern (MID) AF: 0.483 AC: 142 AN: 294

European-Non Finnish (NFE) AF: 0.727 AC: 49390 AN: 67982

Other (OTH) AF: 0.589 AC: 1245 AN: 2114

Alfa AF: 0.675 Hom.: 21008

Bravo AF: 0.553

Asia WGS AF: 0.637 AC: 2211 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 13, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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. -

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Timothy syndrome Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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

Sep 04, 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	0.0040
DANN	Benign	0.90
PhyloP100		-3.8
Mutation Taster		=89/11	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1051375; hg19: chr12-2788879; COSMIC: COSV59695567; COSMIC: COSV59695567;