rs1131692329

Variant names:

• chr12-2664846-G-A
• rs1131692329
• NM_000719.7:c.4254G>A

Variant summary

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

The NM_000719.7(CACNA1C):​c.4254G>A​(p.Trp1418*) variant causes a stop gained 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 (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CACNA1C NM_000719.7 stop_gained
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 10.0
• 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 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.4254G>A	p.Trp1418*	stop_gained	Exon 35 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.4254G>A	p.Trp1418*	stop_gained	Exon 35 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.4254G>A	p.Trp1418*	stop_gained	Exon 35 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.4254G>A	p.Trp1418*	stop_gained	Exon 35 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.4488G>A	p.Trp1496*	stop_gained	Exon 37 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.4254G>A	p.Trp1418*	stop_gained	Exon 35 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.4221G>A	p.Trp1407*	stop_gained	Exon 34 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.4419G>A	p.Trp1473*	stop_gained	Exon 36 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.4398G>A	p.Trp1466*	stop_gained	Exon 37 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.4320G>A	p.Trp1440*	stop_gained	Exon 35 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.4254G>A	p.Trp1418*	stop_gained	Exon 35 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.4254G>A	p.Trp1418*	stop_gained	Exon 35 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.4344G>A	p.Trp1448*	stop_gained	Exon 35 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.4344G>A	p.Trp1448*	stop_gained	Exon 35 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.4344G>A	p.Trp1448*	stop_gained	Exon 35 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.4344G>A	p.Trp1448*	stop_gained	Exon 35 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.4338G>A	p.Trp1446*	stop_gained	Exon 36 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.4329G>A	p.Trp1443*	stop_gained	Exon 36 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.4314G>A	p.Trp1438*	stop_gained	Exon 36 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.4254G>A	p.Trp1418*	stop_gained	Exon 35 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.4254G>A	p.Trp1418*	stop_gained	Exon 35 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.4254G>A	p.Trp1418*	stop_gained	Exon 35 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.4305G>A	p.Trp1435*	stop_gained	Exon 35 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.4296G>A	p.Trp1432*	stop_gained	Exon 35 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.4221G>A	p.Trp1407*	stop_gained	Exon 34 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.4221G>A	p.Trp1407*	stop_gained	Exon 34 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.4215G>A	p.Trp1405*	stop_gained	Exon 34 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.4254G>A	p.Trp1418*	stop_gained	Exon 35 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.4254G>A	p.Trp1418*	stop_gained	Exon 35 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.4254G>A	p.Trp1418*	stop_gained	Exon 35 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.4254G>A	p.Trp1418*	stop_gained	Exon 35 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.4254G>A	p.Trp1418*	stop_gained	Exon 35 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.4245G>A	p.Trp1415*	stop_gained	Exon 35 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.4221G>A	p.Trp1407*	stop_gained	Exon 34 of 46			ENSP00000507309.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Alfa AF: 0.000117 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Long QT syndrome Uncertain:1

Dec 16, 2016

Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues

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
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	48
DANN	Uncertain	1.0
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		10
Vest4		0.97
GERP RS		4.1
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: rs1131692329; hg19: chr12-2774012;