rs1555881808

Variant names:

• chr12-2606654-CG-C
• rs1555881808
• NM_000719.7:c.3202delG

Variant summary

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

The NM_000719.7(CACNA1C):​c.3202delG​(p.Glu1068AsnfsTer38) variant causes a frameshift change involving the alteration of a non-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, single submitter U:1
• Conservation: PhyloP100: -1.34
• Publications: 0 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-AS3 (HGNC:40117): (CACNA1C antisense RNA 3)

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.3202delG	p.Glu1068AsnfsTer38	frameshift_variant	Exon 25 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.3202delG	p.Glu1068AsnfsTer38	frameshift_variant	Exon 25 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.3202delG	p.Glu1068AsnfsTer38	frameshift_variant	Exon 25 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.3202delG	p.Glu1068AsnfsTer38	frameshift_variant	Exon 25 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.3352delG	p.Glu1118AsnfsTer38	frameshift_variant	Exon 26 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.3202delG	p.Glu1068AsnfsTer38	frameshift_variant	Exon 25 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.3202delG	p.Glu1068AsnfsTer38	frameshift_variant	Exon 25 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.3367delG	p.Glu1123AsnfsTer38	frameshift_variant	Exon 26 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.3262delG	p.Glu1088AsnfsTer38	frameshift_variant	Exon 26 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.3202delG	p.Glu1068AsnfsTer38	frameshift_variant	Exon 25 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.3202delG	p.Glu1068AsnfsTer38	frameshift_variant	Exon 25 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.3202delG	p.Glu1068AsnfsTer38	frameshift_variant	Exon 25 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.3292delG	p.Glu1098AsnfsTer38	frameshift_variant	Exon 25 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.3292delG	p.Glu1098AsnfsTer38	frameshift_variant	Exon 25 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.3292delG	p.Glu1098AsnfsTer38	frameshift_variant	Exon 25 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.3292delG	p.Glu1098AsnfsTer38	frameshift_variant	Exon 25 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.3202delG	p.Glu1068AsnfsTer38	frameshift_variant	Exon 25 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.3277delG	p.Glu1093AsnfsTer38	frameshift_variant	Exon 26 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.3262delG	p.Glu1088AsnfsTer38	frameshift_variant	Exon 26 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.3202delG	p.Glu1068AsnfsTer38	frameshift_variant	Exon 25 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.3202delG	p.Glu1068AsnfsTer38	frameshift_variant	Exon 25 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.3202delG	p.Glu1068AsnfsTer38	frameshift_variant	Exon 25 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.3202delG	p.Glu1068AsnfsTer38	frameshift_variant	Exon 25 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.3277delG	p.Glu1093AsnfsTer38	frameshift_variant	Exon 26 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.3202delG	p.Glu1068AsnfsTer38	frameshift_variant	Exon 25 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.3202delG	p.Glu1068AsnfsTer38	frameshift_variant	Exon 25 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.3202delG	p.Glu1068AsnfsTer38	frameshift_variant	Exon 25 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.3202delG	p.Glu1068AsnfsTer38	frameshift_variant	Exon 25 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.3202delG	p.Glu1068AsnfsTer38	frameshift_variant	Exon 25 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.3202delG	p.Glu1068AsnfsTer38	frameshift_variant	Exon 25 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.3202delG	p.Glu1068AsnfsTer38	frameshift_variant	Exon 25 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.3202delG	p.Glu1068AsnfsTer38	frameshift_variant	Exon 25 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.3193delG	p.Glu1065AsnfsTer38	frameshift_variant	Exon 25 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.3202delG	p.Glu1068AsnfsTer38	frameshift_variant	Exon 25 of 46			ENSP00000507309.1
CACNA1C	ENST00000480911.6	n.*1809delG		non_coding_transcript_exon_variant	Exon 23 of 27	5		ENSP00000437936.2
CACNA1C	ENST00000480911.6	n.*1809delG		3_prime_UTR_variant	Exon 23 of 27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Oct 05, 2016

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.3

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

Other links and lift over

dbSNP: rs1555881808; hg19: chr12-2715820;