rs373503739

Variant names:

• chr12-2688721-G-A
• rs373503739
• NM_000719.7:c.6059G>A

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_000719.7(CACNA1C):​c.6059G>A​(p.Ser2020Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000125 in 1,604,104 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2
• Conservation: PhyloP100: 3.30

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]

CACNA1C-AS1 (HGNC:):

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

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.19330633).
• BP6: Variant 12-2688721-G-A is Benign according to our data. Variant chr12-2688721-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 456992.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=2}.
• BS2: High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.6059G>A	p.Ser2020Asn	missense_variant	Exon 46 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.6059G>A	p.Ser2020Asn	missense_variant	Exon 46 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.6059G>A	p.Ser2020Asn	missense_variant	Exon 46 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.6059G>A	p.Ser2020Asn	missense_variant	Exon 46 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.6398G>A	p.Ser2133Asn	missense_variant	Exon 49 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.6272G>A	p.Ser2091Asn	missense_variant	Exon 47 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.6239G>A	p.Ser2080Asn	missense_variant	Exon 46 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.6224G>A	p.Ser2075Asn	missense_variant	Exon 47 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.6203G>A	p.Ser2068Asn	missense_variant	Exon 48 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.6182G>A	p.Ser2061Asn	missense_variant	Exon 46 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.6164G>A	p.Ser2055Asn	missense_variant	Exon 47 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.6164G>A	p.Ser2055Asn	missense_variant	Exon 47 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.6149G>A	p.Ser2050Asn	missense_variant	Exon 46 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.6149G>A	p.Ser2050Asn	missense_variant	Exon 46 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.6149G>A	p.Ser2050Asn	missense_variant	Exon 46 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.6149G>A	p.Ser2050Asn	missense_variant	Exon 46 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.6143G>A	p.Ser2048Asn	missense_variant	Exon 47 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.6134G>A	p.Ser2045Asn	missense_variant	Exon 47 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.6119G>A	p.Ser2040Asn	missense_variant	Exon 47 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.6116G>A	p.Ser2039Asn	missense_variant	Exon 46 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.6116G>A	p.Ser2039Asn	missense_variant	Exon 46 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.6116G>A	p.Ser2039Asn	missense_variant	Exon 46 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.6110G>A	p.Ser2037Asn	missense_variant	Exon 46 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.6101G>A	p.Ser2034Asn	missense_variant	Exon 46 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.6083G>A	p.Ser2028Asn	missense_variant	Exon 45 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.6083G>A	p.Ser2028Asn	missense_variant	Exon 45 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.6077G>A	p.Ser2026Asn	missense_variant	Exon 45 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.6059G>A	p.Ser2020Asn	missense_variant	Exon 46 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.6059G>A	p.Ser2020Asn	missense_variant	Exon 46 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.6059G>A	p.Ser2020Asn	missense_variant	Exon 46 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.6059G>A	p.Ser2020Asn	missense_variant	Exon 46 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.6059G>A	p.Ser2020Asn	missense_variant	Exon 46 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.6050G>A	p.Ser2017Asn	missense_variant	Exon 46 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.6026G>A	p.Ser2009Asn	missense_variant	Exon 45 of 46			ENSP00000507309.1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152200 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000515 AC: 12 AN: 232940 AF XY: 0.0000627

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.000174

GnomAD4 exome AF: 0.000135 AC: 196 AN: 1451904 Hom.: 0 Cov.: 33 AF XY: 0.000129 AC XY: 93 AN XY: 721272

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 33250

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 44028

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 25768

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39468

Gnomad4 SAS exome AF: 0.0000117 AC: 1 AN: 85596

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 51214

Gnomad4 NFE exome AF: 0.000173 AC: 191 AN: 1106918

Gnomad4 Remaining exome AF: 0.0000501 AC: 3 AN: 59928

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152200 Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3 AN XY: 74338

Gnomad4 AFR AF: 0.0000241 AC: 0.0000241266 AN: 0.0000241266

Gnomad4 AMR AF: 0.00 AC: 0 AN: 0

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.0000588 AC: 0.0000587941 AN: 0.0000587941

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000453

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000122 AC: 1

ExAC AF: 0.0000582 AC: 7

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Long QT syndrome Uncertain:1 Benign:1

Jan 26, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 30, 2016

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

CACNA1C-related disorder Uncertain:1

Feb 08, 2023

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CACNA1C c.6059G>A variant is predicted to result in the amino acid substitution p.Ser2020Asn. This variant was reported in a case of sudden cardiac death; however, this individual also harbored a missense variant in the ANK2 gene (Patient #SD_2 in Table S1, Brion et al. 2014. PubMed ID: 24981977). This variant is reported in 0.010% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/12-2797887-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not provided Uncertain:1

Jan 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Oct 21, 2023

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
CardioboostArm	Benign	0.0000049
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.011	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.;T
Eigen	Benign	0.0070
Eigen_PC	Benign	0.051
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.064	D
MetaRNN	Benign	0.19	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.71	T
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.5	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;.
REVEL	Benign	0.12
Sift	Benign	0.088	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;.
Sift4G	Benign	0.19	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.66, 0.24, 0.14, 0.28, 0.71, 0.43, 0.85, 0.57, 0.76, 0.94, 0.49	.;P;B;B;B;P;B;P;P;P;P;P;P;P;P;.;P;P;.;.;.;P;.
Vest4		0.38
MVP		0.65
MPC		0.19
ClinPred		0.14	T
GERP RS		4.3
gMVP		0.51
Mutation Taster		=82/18	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

Publications

LitVar

Other links and lift over

dbSNP: rs373503739; hg19: chr12-2797887;