chr19-13253014-TC-T

Variant names:

• chr19-13253014-TC-T
• rs587776695
• NM_001127222.2:c.4842delG

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_001127222.2(CACNA1A):​c.4842delG​(p.Val1616SerfsTer7) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CACNA1A NM_001127222.2 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: -0.897
• Publications: 1 publications found

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]

CACNA1A Gene-Disease associations (from GenCC):

• episodic ataxia type 2

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• undetermined early-onset epileptic encephalopathy

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, Illumina
• developmental and epileptic encephalopathy, 42

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• migraine, familial hemiplegic, 1

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• spinocerebellar ataxia type 6

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
• benign paroxysmal torticollis of infancy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial or sporadic hemiplegic migraine

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Lennox-Gastaut syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 11 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 19-13253014-TC-T is Pathogenic according to our data. Variant chr19-13253014-TC-T is described in ClinVar as Pathogenic. ClinVar VariationId is 8502.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.4842delG	p.Val1616SerfsTer7	frameshift_variant	Exon 30 of 47	ENST00000360228.11	NP_001120694.1
CACNA1A	NM_001127221.2	c.4845delG	p.Val1617SerfsTer7	frameshift_variant	Exon 30 of 47	ENST00000638009.2	NP_001120693.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.4842delG	p.Val1616SerfsTer7	frameshift_variant	Exon 30 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638009.2	c.4845delG	p.Val1617SerfsTer7	frameshift_variant	Exon 30 of 47	1	NM_001127221.2	ENSP00000489913.1
CACNA1A	ENST00000638029.1	c.4854delG	p.Val1620SerfsTer7	frameshift_variant	Exon 30 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.4848delG	p.Val1618SerfsTer7	frameshift_variant	Exon 30 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.4845delG	p.Val1617SerfsTer7	frameshift_variant	Exon 30 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.4845delG	p.Val1617SerfsTer7	frameshift_variant	Exon 30 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.4845delG	p.Val1617SerfsTer7	frameshift_variant	Exon 30 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.4704delG	p.Val1570SerfsTer7	frameshift_variant	Exon 29 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.4845delG	p.Val1617SerfsTer7	frameshift_variant	Exon 30 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.4854delG	p.Val1620SerfsTer7	frameshift_variant	Exon 30 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.4845delG	p.Val1617SerfsTer7	frameshift_variant	Exon 30 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.4848delG	p.Val1618SerfsTer7	frameshift_variant	Exon 30 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.4845delG	p.Val1617SerfsTer7	frameshift_variant	Exon 30 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000637276.1	c.4845delG	p.Val1617SerfsTer7	frameshift_variant	Exon 30 of 46	5		ENSP00000489777.1
CACNA1A	ENST00000636768.2	n.4845delG		non_coding_transcript_exon_variant	Exon 30 of 45	5		ENSP00000490190.2
CACNA1A	ENST00000713789.1	n.4842delG		non_coding_transcript_exon_variant	Exon 30 of 47			ENSP00000519091.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Episodic ataxia type 2 Pathogenic:1

Apr 01, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.90
Mutation Taster		=1/199	disease causing (ClinVar)

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: rs587776695; hg19: chr19-13363828;