rs199473391

chr12-2607117-G-Achr12-2607117-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP2 PP3_Moderate

The NM_000719.7(CACNA1C):c.3343G>A(p.Glu1115Lys) 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. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E1115G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:2 O:2
• Conservation: PhyloP100: 9.60

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-AS3 (HGNC:40117): (CACNA1C antisense RNA 3)

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a region_of_interest Dihydropyridine binding (size 89) in uniprot entity CAC1C_HUMAN there are 10 pathogenic changes around while only 3 benign (77%) in NM_000719.7
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, CACNA1C
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.888

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1C	NM_000719.7	c.3343G>A	p.Glu1115Lys	missense_variant	26/47	ENST00000399655.6
CACNA1C	NM_001167623.2	c.3343G>A	p.Glu1115Lys	missense_variant	26/47	ENST00000399603.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1C	ENST00000399603.6	c.3343G>A	p.Glu1115Lys	missense_variant	26/47	5	NM_001167623.2
CACNA1C	ENST00000399655.6	c.3343G>A	p.Glu1115Lys	missense_variant	26/47	1	NM_000719.7
CACNA1C-AS3	ENST00000543559.1	n.20+304C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:2 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Timothy syndrome Pathogenic:1 Other:1

not provided, no classification provided	literature only	GeneReviews	-	Brugada syndrome -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 29, 2022	- -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 20, 2022

- -

Long QT syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 19, 2019

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. This variant has been reported to affect CACNA1C protein function (PMID: 30172029). This variant has been observed in individuals with Brugada syndrome and individuals with long QT syndrome (LQTS) (PMID: 20817017, 30662450, 30172029, Invitae). ClinVar contains an entry for this variant (Variation ID: 67554). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamic acid with lysine at codon 1115 of the CACNA1C protein (p.Glu1115Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. -

Brugada syndrome Other:1

not provided, no classification provided

literature only

Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust

-

This variant has been reported as associated with Brugada syndrome in the following publications (PMID:20817017). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
CardioboostArm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
Cadd	Pathogenic	33
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.68	D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.58	D
MetaRNN	Pathogenic	0.89	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
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-3.8	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	0.95
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0010	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, 0.99, 1.0, 1.0	.;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.;D;D;.;.;.;D
Vest4		0.84
MutPred		0.76		.;.;.;.;.;.;.;.;.;.;.;Gain of catalytic residue at S1132 (P = 0);Gain of catalytic residue at S1132 (P = 0);.;.;.;.;.;.;.;.;.;.;
MVP		0.98
MPC		2.3
ClinPred		0.99	D
GERP RS		4.9
gMVP		1.0

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: rs199473391; hg19: chr12-2716283; COSMIC: COSV59750786; COSMIC: COSV59750786;