chr12-2585473-G-A

Variant names:

• chr12-2585473-G-A
• rs545511851
• NM_000719.7:c.2437G>A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2 BS2

The NM_000719.7(CACNA1C):​c.2437G>A​(p.Gly813Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000159 in 1,570,584 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:1
• Conservation: PhyloP100: 7.77

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 Likely_benign. Variant got -3 ACMG points.

• PP2: Missense variant in the CACNA1C gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 45 curated pathogenic missense variants (we use a threshold of 10). The gene has 91 curated benign missense variants. Gene score misZ: 6.4654 (above the threshold of 3.09). Trascript score misZ: 7.2674 (above the threshold of 3.09). GenCC associations: The gene is linked to intellectual disability, neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizures, Brugada syndrome, long QT syndrome, short QT syndrome, long qt syndrome 8, Timothy syndrome, Brugada syndrome 3.
• BS2: High AC in GnomAdExome4 at 21 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.2437G>A	p.Gly813Arg	missense_variant	Exon 17 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.2437G>A	p.Gly813Arg	missense_variant	Exon 17 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.2437G>A	p.Gly813Arg	missense_variant	Exon 17 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.2437G>A	p.Gly813Arg	missense_variant	Exon 17 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.2527G>A	p.Gly843Arg	missense_variant	Exon 17 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.2437G>A	p.Gly813Arg	missense_variant	Exon 17 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.2437G>A	p.Gly813Arg	missense_variant	Exon 17 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.2602G>A	p.Gly868Arg	missense_variant	Exon 18 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.2437G>A	p.Gly813Arg	missense_variant	Exon 17 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.2437G>A	p.Gly813Arg	missense_variant	Exon 17 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.2437G>A	p.Gly813Arg	missense_variant	Exon 17 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.2437G>A	p.Gly813Arg	missense_variant	Exon 17 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.2527G>A	p.Gly843Arg	missense_variant	Exon 17 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.2527G>A	p.Gly843Arg	missense_variant	Exon 17 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.2527G>A	p.Gly843Arg	missense_variant	Exon 17 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.2527G>A	p.Gly843Arg	missense_variant	Exon 17 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.2437G>A	p.Gly813Arg	missense_variant	Exon 17 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.2512G>A	p.Gly838Arg	missense_variant	Exon 18 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.2437G>A	p.Gly813Arg	missense_variant	Exon 17 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.2437G>A	p.Gly813Arg	missense_variant	Exon 17 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.2437G>A	p.Gly813Arg	missense_variant	Exon 17 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.2437G>A	p.Gly813Arg	missense_variant	Exon 17 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.2437G>A	p.Gly813Arg	missense_variant	Exon 17 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.2512G>A	p.Gly838Arg	missense_variant	Exon 18 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.2437G>A	p.Gly813Arg	missense_variant	Exon 17 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.2437G>A	p.Gly813Arg	missense_variant	Exon 17 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.2437G>A	p.Gly813Arg	missense_variant	Exon 17 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.2437G>A	p.Gly813Arg	missense_variant	Exon 17 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.2437G>A	p.Gly813Arg	missense_variant	Exon 17 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.2437G>A	p.Gly813Arg	missense_variant	Exon 17 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.2437G>A	p.Gly813Arg	missense_variant	Exon 17 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.2437G>A	p.Gly813Arg	missense_variant	Exon 17 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.2428G>A	p.Gly810Arg	missense_variant	Exon 17 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.2437G>A	p.Gly813Arg	missense_variant	Exon 17 of 46			ENSP00000507309.1
CACNA1C	ENST00000480911.6	n.*1044G>A		non_coding_transcript_exon_variant	Exon 15 of 27	5		ENSP00000437936.2
CACNA1C	ENST00000480911.6	n.*1044G>A		3_prime_UTR_variant	Exon 15 of 27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152186 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000336 AC: 6 AN: 178656 Hom.: 0 AF XY: 0.0000314 AC XY: 3 AN XY: 95640

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 SAS exome AF: 0.0000824

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000545

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000148 AC: 21 AN: 1418280 Hom.: 0 Cov.: 31 AF XY: 0.00000855 AC XY: 6 AN XY: 701608

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000247

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000174

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152304 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74478

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000903 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.0000169 AC: 2

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:4

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 18, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in association with LQTS in published literature (Marschall et al., 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31737537) -

-

Clinical Genetics, Academic Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Timothy syndrome;C2678478:Brugada syndrome 3;CN260585:Long qt syndrome 8 Uncertain:1

Aug 10, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Timothy syndrome Uncertain:1

May 08, 2018

Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Long QT syndrome Benign:1

Jun 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.056	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.
Eigen	Pathogenic	0.68
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.58	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Uncertain	2.7	.;M;.;M;M;M;M;M;M;M;M;M;M;M;M;M;.;M;M;M;.;.;.
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-3.2	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.61
Sift	Uncertain	0.018	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Benign	0.17	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		1.0, 0.024, 1.0, 0.90, 1.0, 0.22	.;D;D;B;D;P;D;D;D;B;D;D;D;D;D;D;.;D;D;.;D;.;D
Vest4		0.72
MutPred		0.31		.;Gain of catalytic residue at P816 (P = 5e-04);Gain of catalytic residue at P816 (P = 5e-04);Gain of catalytic residue at P816 (P = 5e-04);Gain of catalytic residue at P816 (P = 5e-04);Gain of catalytic residue at P816 (P = 5e-04);Gain of catalytic residue at P816 (P = 5e-04);Gain of catalytic residue at P816 (P = 5e-04);Gain of catalytic residue at P816 (P = 5e-04);Gain of catalytic residue at P816 (P = 5e-04);Gain of catalytic residue at P816 (P = 5e-04);Gain of catalytic residue at P816 (P = 5e-04);Gain of catalytic residue at P816 (P = 5e-04);Gain of catalytic residue at P816 (P = 5e-04);Gain of catalytic residue at P816 (P = 5e-04);Gain of catalytic residue at P816 (P = 5e-04);Gain of catalytic residue at P816 (P = 5e-04);Gain of catalytic residue at P816 (P = 5e-04);Gain of catalytic residue at P816 (P = 5e-04);Gain of catalytic residue at P816 (P = 5e-04);Gain of catalytic residue at P816 (P = 5e-04);Gain of catalytic residue at P816 (P = 5e-04);Gain of catalytic residue at P816 (P = 5e-04);
MVP		0.94
MPC		2.2
ClinPred		0.41	T
GERP RS		5.8
gMVP		0.63

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: rs545511851; hg19: chr12-2694639; COSMIC: COSV59763772;