rs1555757523

Variant names:

• chr19-13303831-CT-C
• rs1555757523
• NM_001127222.2:c.2039delA

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001127222.2(CACNA1A):​c.2039delA​(p.Gln680ArgfsTer17) variant causes a frameshift change. 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: 30)
• Consequence: CACNA1A NM_001127222.2 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 4.91

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 18 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 19-13303831-CT-C is Pathogenic according to our data. Variant chr19-13303831-CT-C is described in ClinVar as [Pathogenic]. Clinvar id is 476239.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.2039delA	p.Gln680ArgfsTer17	frameshift_variant	Exon 16 of 47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.2039delA	p.Gln680ArgfsTer17	frameshift_variant	Exon 16 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.2042delA	p.Gln681ArgfsTer17	frameshift_variant	Exon 16 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.2045delA	p.Gln682ArgfsTer17	frameshift_variant	Exon 16 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.2042delA	p.Gln681ArgfsTer17	frameshift_variant	Exon 16 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.2042delA	p.Gln681ArgfsTer17	frameshift_variant	Exon 16 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.2042delA	p.Gln681ArgfsTer17	frameshift_variant	Exon 16 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.1901delA	p.Gln634ArgfsTer17	frameshift_variant	Exon 15 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.2042delA	p.Gln681ArgfsTer17	frameshift_variant	Exon 16 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.2042delA	p.Gln681ArgfsTer17	frameshift_variant	Exon 16 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.2042delA	p.Gln681ArgfsTer17	frameshift_variant	Exon 16 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.2045delA	p.Gln682ArgfsTer17	frameshift_variant	Exon 16 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.2042delA	p.Gln681ArgfsTer17	frameshift_variant	Exon 16 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.2042delA	p.Gln681ArgfsTer17	frameshift_variant	Exon 16 of 47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.2042delA	p.Gln681ArgfsTer17	frameshift_variant	Exon 16 of 46	5		ENSP00000489777.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 30

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Jul 01, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Gln681Argfs*17) 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 conditions. ClinVar contains an entry for this variant (Variation ID: 476239). 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. -

not provided Pathogenic:1

Jun 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Developmental and epileptic encephalopathy, 42 Pathogenic:1

Jun 19, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CACNA1A c.2042delA (p.Gln681ArgfsX17) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 249244 control chromosomes (gnomAD). c.2042delA has been reported in the literature in 2 sisters affected with episodic ataxia and intellectual deficiency (Humbertclaude_2018). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 29926469). Two ClinVar submitters have assessed the variant since 2014: both classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs1555757523; hg19: chr19-13414645;