rs1555756737

Variant names:

• chr19-13300638-C-A
• rs1555756737
• NM_001127222.2:c.2191G>T

Your query was ambiguous. Multiple possible variants found:

• chr19-13300638-C-A
• chr19-13300638-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001127222.2(CACNA1A):​c.2191G>T​(p.Glu731*) variant causes a stop gained change. 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 Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CACNA1A NM_001127222.2 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.11

Genes affected

CACNA1A (HGNC:1388): (calcium voltage-gated channel subunit alpha1 A) Voltage-dependent calcium channels mediate the entry of calcium ions into excitable cells, and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, and gene expression. Calcium channels are multisubunit complexes composed of alpha-1, beta, alpha-2/delta, and gamma subunits. The channel activity is directed by the pore-forming alpha-1 subunit, whereas, the others act as auxiliary subunits regulating this activity. The distinctive properties of the calcium channel types are related primarily to the expression of a variety of alpha-1 isoforms, alpha-1A, B, C, D, E, and S. This gene encodes the alpha-1A subunit, which is predominantly expressed in neuronal tissue. Mutations in this gene are associated with 2 neurologic disorders, familial hemiplegic migraine and episodic ataxia 2. This gene also exhibits polymorphic variation due to (CAG)n-repeats. Multiple transcript variants encoding different isoforms have been found for this gene. In one set of transcript variants, the (CAG)n-repeats occur in the 3' UTR, and are not associated with any disease. But in another set of variants, an insertion extends the coding region to include the (CAG)n-repeats which encode a polyglutamine tract. Expansion of the (CAG)n-repeats from the normal 4-18 to 21-33 in the coding region is associated with spinocerebellar ataxia 6. [provided by RefSeq, Jul 2016]

ACMG classification

Verdict is Pathogenic. Variant got 12 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
• PP5: Variant 19-13300638-C-A is Pathogenic according to our data. Variant chr19-13300638-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 542827.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.2191G>T	p.Glu731*	stop_gained	Exon 18 of 47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.2191G>T	p.Glu731*	stop_gained	Exon 18 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.2203G>T	p.Glu735*	stop_gained	Exon 18 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.2197G>T	p.Glu733*	stop_gained	Exon 18 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.2194G>T	p.Glu732*	stop_gained	Exon 18 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.2194G>T	p.Glu732*	stop_gained	Exon 18 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.2194G>T	p.Glu732*	stop_gained	Exon 18 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.2053G>T	p.Glu685*	stop_gained	Exon 17 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.2194G>T	p.Glu732*	stop_gained	Exon 18 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.2203G>T	p.Glu735*	stop_gained	Exon 18 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.2194G>T	p.Glu732*	stop_gained	Exon 18 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.2197G>T	p.Glu733*	stop_gained	Exon 18 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.2194G>T	p.Glu732*	stop_gained	Exon 18 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.2194G>T	p.Glu732*	stop_gained	Exon 18 of 47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.2194G>T	p.Glu732*	stop_gained	Exon 18 of 46	5		ENSP00000489777.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Episodic ataxia type 2;C4310716:Developmental and epileptic encephalopathy, 42 Pathogenic:1

Jan 04, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in CACNA1A are known to be pathogenic (PMID: 10371528, 19486177, 25735478, 27250579). This variant has not been reported in the literature in individuals with CACNA1A-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Glu732*) in the CACNA1A gene. It is expected to result in an absent or disrupted protein product. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	47
DANN	Uncertain	1.0
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Uncertain	0.96	D
Vest4		0.83
GERP RS		4.9

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1555756737; hg19: chr19-13411452;