NM_000719.7:c.2278G>A

Variant names:

• chr12-2584556-G-A
• rs1555832882
• NM_000719.7:c.2278G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000719.7(CACNA1C):​c.2278G>A​(p.Glu760Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. E760E) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.98
• 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]

CACNA1C Gene-Disease associations (from GenCC):

• Timothy syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizures

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
• long QT syndrome

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• long QT syndrome 8

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• Brugada syndrome

  Inheritance: AD Classification: SUPPORTIVE, NO_KNOWN Submitted by: Orphanet, ClinGen
• Brugada syndrome 3

  Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• intellectual disability

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• short QT syndrome

  Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Ambry Genetics, ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.871

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.2278G>A	p.Glu760Lys	missense_variant	Exon 16 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.2278G>A	p.Glu760Lys	missense_variant	Exon 16 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.2278G>A	p.Glu760Lys	missense_variant	Exon 16 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.2278G>A	p.Glu760Lys	missense_variant	Exon 16 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.2368G>A	p.Glu790Lys	missense_variant	Exon 16 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.2278G>A	p.Glu760Lys	missense_variant	Exon 16 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.2278G>A	p.Glu760Lys	missense_variant	Exon 16 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.2443G>A	p.Glu815Lys	missense_variant	Exon 17 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.2278G>A	p.Glu760Lys	missense_variant	Exon 16 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.2278G>A	p.Glu760Lys	missense_variant	Exon 16 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.2278G>A	p.Glu760Lys	missense_variant	Exon 16 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.2278G>A	p.Glu760Lys	missense_variant	Exon 16 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.2368G>A	p.Glu790Lys	missense_variant	Exon 16 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.2368G>A	p.Glu790Lys	missense_variant	Exon 16 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.2368G>A	p.Glu790Lys	missense_variant	Exon 16 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.2368G>A	p.Glu790Lys	missense_variant	Exon 16 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.2278G>A	p.Glu760Lys	missense_variant	Exon 16 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.2353G>A	p.Glu785Lys	missense_variant	Exon 17 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.2278G>A	p.Glu760Lys	missense_variant	Exon 16 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.2278G>A	p.Glu760Lys	missense_variant	Exon 16 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.2278G>A	p.Glu760Lys	missense_variant	Exon 16 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.2278G>A	p.Glu760Lys	missense_variant	Exon 16 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.2278G>A	p.Glu760Lys	missense_variant	Exon 16 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.2353G>A	p.Glu785Lys	missense_variant	Exon 17 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.2278G>A	p.Glu760Lys	missense_variant	Exon 16 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.2278G>A	p.Glu760Lys	missense_variant	Exon 16 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.2278G>A	p.Glu760Lys	missense_variant	Exon 16 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.2278G>A	p.Glu760Lys	missense_variant	Exon 16 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.2278G>A	p.Glu760Lys	missense_variant	Exon 16 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.2278G>A	p.Glu760Lys	missense_variant	Exon 16 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.2278G>A	p.Glu760Lys	missense_variant	Exon 16 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.2278G>A	p.Glu760Lys	missense_variant	Exon 16 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.2269G>A	p.Glu757Lys	missense_variant	Exon 16 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.2278G>A	p.Glu760Lys	missense_variant	Exon 16 of 46			ENSP00000507309.1
CACNA1C	ENST00000480911.6	n.*885G>A		non_coding_transcript_exon_variant	Exon 14 of 27	5		ENSP00000437936.2
CACNA1C	ENST00000480911.6	n.*885G>A		3_prime_UTR_variant	Exon 14 of 27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Long QT syndrome Uncertain:1

Dec 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 760 of the CACNA1C protein (p.Glu760Lys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CACNA1C-related conditions. ClinVar contains an entry for this variant (Variation ID: 526937). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt CACNA1C protein function with a positive predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
CardioboostArm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.67	D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.67	D
MetaRNN	Pathogenic	0.87	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	1.1	D
MutationAssessor	Uncertain	2.9	.;M;.;M;M;M;M;M;M;M;M;M;M;M;M;M;.;M;M;M;.;.;.
PhyloP100		10
PrimateAI	Pathogenic	0.93	D
PROVEAN	Uncertain	-3.7	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0020	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.0050	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		1.0, 0.97, 0.89, 1.0, 1.0, 0.93, 1.0, 0.98, 0.99	.;D;D;P;D;P;D;D;D;P;D;D;D;D;D;D;.;D;D;.;D;.;D
Vest4		0.92
MutPred		0.45		.;Gain of ubiquitination at E760 (P = 0.0037);Gain of ubiquitination at E760 (P = 0.0037);Gain of ubiquitination at E760 (P = 0.0037);Gain of ubiquitination at E760 (P = 0.0037);Gain of ubiquitination at E760 (P = 0.0037);Gain of ubiquitination at E760 (P = 0.0037);Gain of ubiquitination at E760 (P = 0.0037);Gain of ubiquitination at E760 (P = 0.0037);Gain of ubiquitination at E760 (P = 0.0037);Gain of ubiquitination at E760 (P = 0.0037);Gain of ubiquitination at E760 (P = 0.0037);Gain of ubiquitination at E760 (P = 0.0037);Gain of ubiquitination at E760 (P = 0.0037);Gain of ubiquitination at E760 (P = 0.0037);Gain of ubiquitination at E760 (P = 0.0037);Gain of ubiquitination at E760 (P = 0.0037);Gain of ubiquitination at E760 (P = 0.0037);Gain of ubiquitination at E760 (P = 0.0037);Gain of ubiquitination at E760 (P = 0.0037);Gain of ubiquitination at E760 (P = 0.0037);Gain of ubiquitination at E760 (P = 0.0037);Gain of ubiquitination at E760 (P = 0.0037);
MVP		0.97
MPC		2.3
ClinPred		1.0	D
GERP RS		4.7
gMVP		0.96
Mutation Taster		=30/70	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1555832882; hg19: chr12-2693722; COSMIC: COSV100214579;