chr12-2682583-G-A

Variant names:

• chr12-2682583-G-A
• rs200283756
• NM_000719.7:c.5478G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000719.7(CACNA1C):​c.5478G>A​(p.Ala1826Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000237 in 1,612,498 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00023 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00024 (0 hom.)
• Consequence: CACNA1C NM_000719.7 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.55
• Publications: 4 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=-0.52).
• BP6: Variant 12-2682583-G-A is Benign according to our data. Variant chr12-2682583-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 190625.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.55 with no splicing effect.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000238 (347/1460274) while in subpopulation MID AF = 0.00156 (9/5762). AF 95% confidence interval is 0.000815. There are 0 homozygotes in GnomAdExome4. There are 163 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 35 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.5478G>A	p.Ala1826Ala	synonymous_variant	Exon 43 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.5478G>A	p.Ala1826Ala	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.5478G>A	p.Ala1826Ala	synonymous_variant	Exon 43 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.5478G>A	p.Ala1826Ala	synonymous_variant	Exon 43 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.5817G>A	p.Ala1939Ala	synonymous_variant	Exon 46 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.5691G>A	p.Ala1897Ala	synonymous_variant	Exon 44 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.5658G>A	p.Ala1886Ala	synonymous_variant	Exon 43 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.5643G>A	p.Ala1881Ala	synonymous_variant	Exon 44 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.5622G>A	p.Ala1874Ala	synonymous_variant	Exon 45 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.5601G>A	p.Ala1867Ala	synonymous_variant	Exon 43 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.5583G>A	p.Ala1861Ala	synonymous_variant	Exon 44 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.5583G>A	p.Ala1861Ala	synonymous_variant	Exon 44 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.5568G>A	p.Ala1856Ala	synonymous_variant	Exon 43 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.5568G>A	p.Ala1856Ala	synonymous_variant	Exon 43 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.5568G>A	p.Ala1856Ala	synonymous_variant	Exon 43 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.5568G>A	p.Ala1856Ala	synonymous_variant	Exon 43 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.5562G>A	p.Ala1854Ala	synonymous_variant	Exon 44 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.5553G>A	p.Ala1851Ala	synonymous_variant	Exon 44 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.5538G>A	p.Ala1846Ala	synonymous_variant	Exon 44 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.5535G>A	p.Ala1845Ala	synonymous_variant	Exon 43 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.5535G>A	p.Ala1845Ala	synonymous_variant	Exon 43 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.5535G>A	p.Ala1845Ala	synonymous_variant	Exon 43 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.5529G>A	p.Ala1843Ala	synonymous_variant	Exon 43 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.5520G>A	p.Ala1840Ala	synonymous_variant	Exon 43 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.5502G>A	p.Ala1834Ala	synonymous_variant	Exon 42 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.5502G>A	p.Ala1834Ala	synonymous_variant	Exon 42 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.5496G>A	p.Ala1832Ala	synonymous_variant	Exon 42 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.5478G>A	p.Ala1826Ala	synonymous_variant	Exon 43 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.5478G>A	p.Ala1826Ala	synonymous_variant	Exon 43 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.5478G>A	p.Ala1826Ala	synonymous_variant	Exon 43 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.5478G>A	p.Ala1826Ala	synonymous_variant	Exon 43 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.5478G>A	p.Ala1826Ala	synonymous_variant	Exon 43 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.5469G>A	p.Ala1823Ala	synonymous_variant	Exon 43 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.5445G>A	p.Ala1815Ala	synonymous_variant	Exon 42 of 46			ENSP00000507309.1

Frequencies

GnomAD3 genomes AF: 0.000230 AC: 35 AN: 152106 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.0121

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: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000292 AC: 72 AN: 246556 AF XY: 0.000254

Gnomad AFR exome AF: 0.0000654

Gnomad AMR exome AF: 0.00108

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000250

Gnomad OTH exome AF: 0.000668

GnomAD4 exome AF: 0.000238 AC: 347 AN: 1460274 Hom.: 0 Cov.: 31 AF XY: 0.000224 AC XY: 163 AN XY: 726334

African (AFR) AF: 0.0000299 AC: 1 AN: 33472

American (AMR) AF: 0.000964 AC: 43 AN: 44592

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26104

East Asian (EAS) AF: 0.00 AC: 0 AN: 39672

South Asian (SAS) AF: 0.0000465 AC: 4 AN: 86066

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52844

Middle Eastern (MID) AF: 0.00156 AC: 9 AN: 5762

European-Non Finnish (NFE) AF: 0.000246 AC: 273 AN: 1111426

Other (OTH) AF: 0.000282 AC: 17 AN: 60336

GnomAD4 genome AF: 0.000230 AC: 35 AN: 152224 Hom.: 0 Cov.: 32 AF XY: 0.000269 AC XY: 20 AN XY: 74418

African (AFR) AF: 0.0000481 AC: 2 AN: 41542

American (AMR) AF: 0.000196 AC: 3 AN: 15296

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000279 AC: 19 AN: 68006

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.000341 Hom.: 0

Bravo AF: 0.000397

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Feb 28, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CACNA1C: BP4, BP7 -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Apr 10, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Oct 19, 2023

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

CACNA1C-related disorder Benign:1

Feb 08, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Long QT syndrome Benign:1

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Jun 06, 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	-0.52
CADD	Benign	5.6
DANN	Benign	0.60
PhyloP100		1.6
Mutation Taster		=100/0	polymorphism

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: rs200283756; hg19: chr12-2791749;