chr12-2668972-A-ACAGT

Variant names:

• chr12-2668972-A-ACAGT
• rs2096394881
• NM_000719.7:c.4666_4669dupGTCA

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_000719.7(CACNA1C):​c.4666_4669dupGTCA​(p.Met1557SerfsTer28) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CACNA1C NM_000719.7 frameshift
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.91

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-AS2 (HGNC:):

CACNA1C-AS2 (HGNC:40118): (CACNA1C antisense RNA 2)

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.4666_4669dupGTCA	p.Met1557SerfsTer28	frameshift_variant	Exon 38 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.4666_4669dupGTCA	p.Met1557SerfsTer28	frameshift_variant	Exon 38 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.4666_4669dupGTCA	p.Met1557SerfsTer28	frameshift_variant	Exon 38 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.4666_4669dupGTCA	p.Met1557SerfsTer28	frameshift_variant	Exon 38 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.4900_4903dupGTCA	p.Met1635SerfsTer28	frameshift_variant	Exon 40 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.4666_4669dupGTCA	p.Met1557SerfsTer28	frameshift_variant	Exon 38 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.4633_4636dupGTCA	p.Met1546SerfsTer28	frameshift_variant	Exon 37 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.4831_4834dupGTCA	p.Met1612SerfsTer28	frameshift_variant	Exon 39 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.4810_4813dupGTCA	p.Met1605SerfsTer28	frameshift_variant	Exon 40 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.4732_4735dupGTCA	p.Met1579SerfsTer33	frameshift_variant	Exon 38 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.4666_4669dupGTCA	p.Met1557SerfsTer28	frameshift_variant	Exon 38 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.4666_4669dupGTCA	p.Met1557SerfsTer28	frameshift_variant	Exon 38 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.4756_4759dupGTCA	p.Met1587SerfsTer28	frameshift_variant	Exon 38 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.4756_4759dupGTCA	p.Met1587SerfsTer28	frameshift_variant	Exon 38 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.4756_4759dupGTCA	p.Met1587SerfsTer28	frameshift_variant	Exon 38 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.4756_4759dupGTCA	p.Met1587SerfsTer28	frameshift_variant	Exon 38 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.4750_4753dupGTCA	p.Met1585SerfsTer28	frameshift_variant	Exon 39 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.4741_4744dupGTCA	p.Met1582SerfsTer28	frameshift_variant	Exon 39 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.4726_4729dupGTCA	p.Met1577SerfsTer28	frameshift_variant	Exon 39 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.4666_4669dupGTCA	p.Met1557SerfsTer33	frameshift_variant	Exon 38 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.4666_4669dupGTCA	p.Met1557SerfsTer33	frameshift_variant	Exon 38 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.4666_4669dupGTCA	p.Met1557SerfsTer33	frameshift_variant	Exon 38 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.4717_4720dupGTCA	p.Met1574SerfsTer28	frameshift_variant	Exon 38 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.4708_4711dupGTCA	p.Met1571SerfsTer28	frameshift_variant	Exon 38 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.4633_4636dupGTCA	p.Met1546SerfsTer33	frameshift_variant	Exon 37 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.4633_4636dupGTCA	p.Met1546SerfsTer33	frameshift_variant	Exon 37 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.4627_4630dupGTCA	p.Met1544SerfsTer33	frameshift_variant	Exon 37 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.4666_4669dupGTCA	p.Met1557SerfsTer28	frameshift_variant	Exon 38 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.4666_4669dupGTCA	p.Met1557SerfsTer28	frameshift_variant	Exon 38 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.4666_4669dupGTCA	p.Met1557SerfsTer28	frameshift_variant	Exon 38 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.4666_4669dupGTCA	p.Met1557SerfsTer28	frameshift_variant	Exon 38 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.4666_4669dupGTCA	p.Met1557SerfsTer28	frameshift_variant	Exon 38 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.4657_4660dupGTCA	p.Met1554SerfsTer28	frameshift_variant	Exon 38 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.4633_4636dupGTCA	p.Met1546SerfsTer28	frameshift_variant	Exon 37 of 46			ENSP00000507309.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Long QT syndrome Uncertain:1

Sep 27, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 sequence change creates a premature translational stop signal (p.Met1557Serfs*28) in the CACNA1C gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in CACNA1C cause disease. 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: 835382). -

Cardiovascular phenotype Uncertain:1

Nov 10, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4666_4669dupGTCA variant, located in coding exon 38 of the CACNA1C gene, results from a duplication of GTCA at nucleotide position 4666, causing a translational frameshift with a predicted alternate stop codon (p.M1557Sfs*28). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. However, loss of function of CACNA1C has not been clearly established as a mechanism of disease. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2096394881; hg19: chr12-2778138;