12-2512978-C-T

Position:

• chr12-2512978-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_000719.7(CACNA1C):​c.1384C>T​(p.Arg462*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,448,092 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CACNA1C NM_000719.7 stop_gained
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.90

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 Pathogenic. Variant got 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/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.1384C>T	p.Arg462*	stop_gained	9/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.1384C>T	p.Arg462*	stop_gained	9/47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.1384C>T	p.Arg462*	stop_gained	9/47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.1384C>T	p.Arg462*	stop_gained	9/47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.1474C>T	p.Arg492*	stop_gained	9/50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.1384C>T	p.Arg462*	stop_gained	9/48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.1384C>T	p.Arg462*	stop_gained	9/47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.1474C>T	p.Arg492*	stop_gained	9/48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.1384C>T	p.Arg462*	stop_gained	9/49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.1384C>T	p.Arg462*	stop_gained	9/47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.1384C>T	p.Arg462*	stop_gained	9/48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.1384C>T	p.Arg462*	stop_gained	9/48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.1474C>T	p.Arg492*	stop_gained	9/47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.1474C>T	p.Arg492*	stop_gained	9/47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.1474C>T	p.Arg492*	stop_gained	9/47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.1474C>T	p.Arg492*	stop_gained	9/47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.1384C>T	p.Arg462*	stop_gained	9/48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.1384C>T	p.Arg462*	stop_gained	9/48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.1384C>T	p.Arg462*	stop_gained	9/48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.1384C>T	p.Arg462*	stop_gained	9/47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.1384C>T	p.Arg462*	stop_gained	9/47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.1384C>T	p.Arg462*	stop_gained	9/47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.1384C>T	p.Arg462*	stop_gained	9/47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.1384C>T	p.Arg462*	stop_gained	9/47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.1384C>T	p.Arg462*	stop_gained	9/46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.1384C>T	p.Arg462*	stop_gained	9/46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.1384C>T	p.Arg462*	stop_gained	9/46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.1384C>T	p.Arg462*	stop_gained	9/47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.1384C>T	p.Arg462*	stop_gained	9/47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.1384C>T	p.Arg462*	stop_gained	9/47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.1384C>T	p.Arg462*	stop_gained	9/47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.1384C>T	p.Arg462*	stop_gained	9/47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.1375C>T	p.Arg459*	stop_gained	9/47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.1384C>T	p.Arg462*	stop_gained	9/46			ENSP00000507309.1
CACNA1C	ENST00000480911.6	n.1113+19592C>T		intron_variant		5		ENSP00000437936.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1448092 Hom.: 0 Cov.: 30 AF XY: 0.00000139 AC XY: 1 AN XY: 718918

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000181

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Long QT syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 11, 2021

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 not been reported in the literature in individuals affected with CACNA1C-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg462*) 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	44
DANN	Uncertain	1.0
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.96	D
Vest4		0.92
GERP RS		3.5

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: rs761430418; hg19: chr12-2622144;