12-2512978-C-T

Variant names:

• chr12-2512978-C-T
• rs761430418
• NM_000719.7:c.1384C>T

Variant summary

Our verdict is Pathogenic. The variant received 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
• Publications: 2 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: 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.1384C>T	p.Arg462*	stop_gained	Exon 9 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.1384C>T	p.Arg462*	stop_gained	Exon 9 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.1384C>T	p.Arg462*	stop_gained	Exon 9 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.1384C>T	p.Arg462*	stop_gained	Exon 9 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.1474C>T	p.Arg492*	stop_gained	Exon 9 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.1384C>T	p.Arg462*	stop_gained	Exon 9 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.1384C>T	p.Arg462*	stop_gained	Exon 9 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.1474C>T	p.Arg492*	stop_gained	Exon 9 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.1384C>T	p.Arg462*	stop_gained	Exon 9 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.1384C>T	p.Arg462*	stop_gained	Exon 9 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.1384C>T	p.Arg462*	stop_gained	Exon 9 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.1384C>T	p.Arg462*	stop_gained	Exon 9 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.1474C>T	p.Arg492*	stop_gained	Exon 9 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.1474C>T	p.Arg492*	stop_gained	Exon 9 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.1474C>T	p.Arg492*	stop_gained	Exon 9 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.1474C>T	p.Arg492*	stop_gained	Exon 9 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.1384C>T	p.Arg462*	stop_gained	Exon 9 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.1384C>T	p.Arg462*	stop_gained	Exon 9 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.1384C>T	p.Arg462*	stop_gained	Exon 9 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.1384C>T	p.Arg462*	stop_gained	Exon 9 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.1384C>T	p.Arg462*	stop_gained	Exon 9 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.1384C>T	p.Arg462*	stop_gained	Exon 9 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.1384C>T	p.Arg462*	stop_gained	Exon 9 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.1384C>T	p.Arg462*	stop_gained	Exon 9 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.1384C>T	p.Arg462*	stop_gained	Exon 9 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.1384C>T	p.Arg462*	stop_gained	Exon 9 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.1384C>T	p.Arg462*	stop_gained	Exon 9 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.1384C>T	p.Arg462*	stop_gained	Exon 9 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.1384C>T	p.Arg462*	stop_gained	Exon 9 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.1384C>T	p.Arg462*	stop_gained	Exon 9 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.1384C>T	p.Arg462*	stop_gained	Exon 9 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.1384C>T	p.Arg462*	stop_gained	Exon 9 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.1375C>T	p.Arg459*	stop_gained	Exon 9 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.1384C>T	p.Arg462*	stop_gained	Exon 9 of 46			ENSP00000507309.1
CACNA1C	ENST00000480911.6	n.1113+19592C>T		intron_variant	Intron 7 of 26	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

African (AFR) AF: 0.00 AC: 0 AN: 33246

American (AMR) AF: 0.00 AC: 0 AN: 42872

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25784

East Asian (EAS) AF: 0.00 AC: 0 AN: 39158

South Asian (SAS) AF: 0.00 AC: 0 AN: 83472

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52540

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5734

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1105360

Other (OTH) AF: 0.00 AC: 0 AN: 59926

GnomAD4 genome Cov.: 32

Alfa AF: 0.000153 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Long QT syndrome Uncertain:1

Nov 11, 2021

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.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. 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.

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
DEOGEN2	Benign	0.0	.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.57
LIST_S2	Benign	0.0	.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
MetaRNN	Benign	0.0	.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
MutationAssessor	Benign	0.0	.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
PhyloP100		1.9
PROVEAN	Benign	0.0	.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift	Pathogenic	0.0	.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Pathogenic	0.0	.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.92
GERP RS		3.5
Mutation Taster		=0/200	disease causing (fs/PTC)

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: rs761430418; hg19: chr12-2622144;