chr12-2682634-T-C

Variant names:

• chr12-2682634-T-C
• rs371831239
• NM_000719.7:c.5529T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_000719.7(CACNA1C):​c.5529T>C​(p.His1843His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000117 in 1,612,300 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: CACNA1C NM_000719.7 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: -0.740
• Publications: 1 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 12-2682634-T-C is Benign according to our data. Variant chr12-2682634-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 136641.
• BP7: Synonymous conserved (PhyloP=-0.74 with no splicing effect.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000121 (177/1460288) while in subpopulation MID AF = 0.00208 (12/5762). AF 95% confidence interval is 0.0012. There are 0 homozygotes in GnomAdExome4. There are 81 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.5529T>C	p.His1843His	synonymous_variant	Exon 43 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.5529T>C	p.His1843His	synonymous_variant	Exon 43 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.5529T>C	p.His1843His	synonymous_variant	Exon 43 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.5529T>C	p.His1843His	synonymous_variant	Exon 43 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.5868T>C	p.His1956His	synonymous_variant	Exon 46 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.5742T>C	p.His1914His	synonymous_variant	Exon 44 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.5709T>C	p.His1903His	synonymous_variant	Exon 43 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.5694T>C	p.His1898His	synonymous_variant	Exon 44 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.5673T>C	p.His1891His	synonymous_variant	Exon 45 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.5652T>C	p.His1884His	synonymous_variant	Exon 43 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.5634T>C	p.His1878His	synonymous_variant	Exon 44 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.5634T>C	p.His1878His	synonymous_variant	Exon 44 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.5619T>C	p.His1873His	synonymous_variant	Exon 43 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.5619T>C	p.His1873His	synonymous_variant	Exon 43 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.5619T>C	p.His1873His	synonymous_variant	Exon 43 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.5619T>C	p.His1873His	synonymous_variant	Exon 43 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.5613T>C	p.His1871His	synonymous_variant	Exon 44 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.5604T>C	p.His1868His	synonymous_variant	Exon 44 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.5589T>C	p.His1863His	synonymous_variant	Exon 44 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.5586T>C	p.His1862His	synonymous_variant	Exon 43 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.5586T>C	p.His1862His	synonymous_variant	Exon 43 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.5586T>C	p.His1862His	synonymous_variant	Exon 43 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.5580T>C	p.His1860His	synonymous_variant	Exon 43 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.5571T>C	p.His1857His	synonymous_variant	Exon 43 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.5553T>C	p.His1851His	synonymous_variant	Exon 42 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.5553T>C	p.His1851His	synonymous_variant	Exon 42 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.5547T>C	p.His1849His	synonymous_variant	Exon 42 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.5529T>C	p.His1843His	synonymous_variant	Exon 43 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.5529T>C	p.His1843His	synonymous_variant	Exon 43 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.5529T>C	p.His1843His	synonymous_variant	Exon 43 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.5529T>C	p.His1843His	synonymous_variant	Exon 43 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.5529T>C	p.His1843His	synonymous_variant	Exon 43 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.5520T>C	p.His1840His	synonymous_variant	Exon 43 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.5496T>C	p.His1832His	synonymous_variant	Exon 42 of 46			ENSP00000507309.1

Frequencies

GnomAD3 genomes AF: 0.0000789 AC: 12 AN: 152012 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000105 AC: 26 AN: 247298 AF XY: 0.000104

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000175

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000151

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000121 AC: 177 AN: 1460288 Hom.: 0 Cov.: 31 AF XY: 0.000112 AC XY: 81 AN XY: 726344

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.000202 AC: 9 AN: 44634

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.000116 AC: 10 AN: 86108

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52534

Middle Eastern (MID) AF: 0.00208 AC: 12 AN: 5762

European-Non Finnish (NFE) AF: 0.000123 AC: 137 AN: 1111618

Other (OTH) AF: 0.000149 AC: 9 AN: 60346

GnomAD4 genome AF: 0.0000789 AC: 12 AN: 152012 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74236

African (AFR) AF: 0.0000242 AC: 1 AN: 41366

American (AMR) AF: 0.000196 AC: 3 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00633 AC: 2 AN: 316

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68000

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000111 Hom.: 0

Bravo AF: 0.000121

EpiCase AF: 0.000382

EpiControl AF: 0.000416

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Sep 22, 2015

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 22, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Nov 19, 2013

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. -

Long QT syndrome Benign:1

Jan 11, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Aug 24, 2016

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely 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	-0.82
CADD	Benign	0.098
DANN	Benign	0.51
PhyloP100		-0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs371831239; hg19: chr12-2791800; COSMIC: COSV59739036; COSMIC: COSV59739036;