rs1555756461

Positions:

• chr19-13299313-ACAC-AGT

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PVS1 PM2 PP2 PP5_Moderate

The NM_001127222.2(CACNA1A):​c.2317_2319delGTGinsAC​(p.Val773fs) variant causes a frameshift, missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 frameshift, missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.84

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 13 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
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CACNA1A. . Gene score misZ: 5.7845 (greater than the threshold 3.09). Trascript score misZ: 3.9354 (greater than threshold 3.09). The gene has 137 curated pathogenic missense variants (we use a threshold of 10). The gene has 132 curated benign missense variants. GenCC has associacion of the gene with benign paroxysmal torticollis of infancy, developmental and epileptic encephalopathy, 42, undetermined early-onset epileptic encephalopathy, episodic ataxia type 2, familial or sporadic hemiplegic migraine, spinocerebellar ataxia type 6, Lennox-Gastaut syndrome, migraine, familial hemiplegic, 1.
• PP5: Variant 19-13299314-CAC-GT is Pathogenic according to our data. Variant chr19-13299314-CAC-GT is described in ClinVar as [Pathogenic]. Clinvar id is 542835.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.2317_2319delGTGinsAC	p.Val773fs	frameshift_variant, missense_variant	19/47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.2317_2319delGTGinsAC	p.Val773fs	frameshift_variant, missense_variant	19/47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.2329_2331delGTGinsAC	p.Val777fs	frameshift_variant, missense_variant	19/48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.2323_2325delGTGinsAC	p.Val775fs	frameshift_variant, missense_variant	19/47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.2320_2322delGTGinsAC	p.Val774fs	frameshift_variant, missense_variant	19/47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.2320_2322delGTGinsAC	p.Val774fs	frameshift_variant, missense_variant	19/47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.2320_2322delGTGinsAC	p.Val774fs	frameshift_variant, missense_variant	19/46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.2179_2181delGTGinsAC	p.Val727fs	frameshift_variant, missense_variant	18/46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.2320_2322delGTGinsAC	p.Val774fs	frameshift_variant, missense_variant	19/47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.2329_2331delGTGinsAC	p.Val777fs	frameshift_variant, missense_variant	19/48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.2320_2322delGTGinsAC	p.Val774fs	frameshift_variant, missense_variant	19/48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.2323_2325delGTGinsAC	p.Val775fs	frameshift_variant, missense_variant	19/47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.2320_2322delGTGinsAC	p.Val774fs	frameshift_variant, missense_variant	19/47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.2320_2322delGTGinsAC	p.Val774fs	frameshift_variant, missense_variant	19/47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.2320_2322delGTGinsAC	p.Val774fs	frameshift_variant, missense_variant	19/46	5		ENSP00000489777.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 12, 2018

This sequence change creates a premature translational stop signal (p.Val774Thrfs*43) in the CACNA1A gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with CACNA1A-related disease. Loss-of-function variants in CACNA1A are known to be pathogenic (PMID: 10371528, 19486177, 25735478, 27250579). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1555756461; hg19: chr19-13410128;