19-13275849-C-G

Position:

• chr19-13275849-C-G

Variant summary

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

The NM_001127222.2(CACNA1A):​c.3989+1G>C variant causes a splice donor, intron 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. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CACNA1A NM_001127222.2 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.80

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 4.9, offset of -32, new splice context is: gtgGTcagt. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-13275849-C-G is Pathogenic according to our data. Variant chr19-13275849-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 981518.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.3989+1G>C		splice_donor_variant, intron_variant		ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.3989+1G>C		splice_donor_variant, intron_variant		1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.4001+1G>C		splice_donor_variant, intron_variant		5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.3995+1G>C		splice_donor_variant, intron_variant		5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.3992+1G>C		splice_donor_variant, intron_variant		5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.3992+1G>C		splice_donor_variant, intron_variant		1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.3992+1G>C		splice_donor_variant, intron_variant		5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.3851+1G>C		splice_donor_variant, intron_variant		5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.3992+1G>C		splice_donor_variant, intron_variant		5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.4001+1G>C		splice_donor_variant, intron_variant		5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.3992+1G>C		splice_donor_variant, intron_variant		5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.3995+1G>C		splice_donor_variant, intron_variant		5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.3992+1G>C		splice_donor_variant, intron_variant		5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.3992+1G>C		splice_donor_variant, intron_variant		1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.3992+1G>C		splice_donor_variant, intron_variant		5		ENSP00000489777.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Episodic ataxia type 2 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Johns Hopkins Genomics, Johns Hopkins University

Sep 24, 2020

This CACNA1A variant is absent in a large population dataset and has an entry in ClinVar. It has been previously reported in a family with episodic ataxia type-2 (EA2), and was identified in the patient symptomatic father. This variant destroys the native donor (5') splice site for exon 24. We consider c.3989+1G>C to be likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	36
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Uncertain	0.95	D
GERP RS		4.6

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.73		Position offset: 33
DS_DL_spliceai		1.0		Position offset: 1

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

Publications

LitVar

Other links and lift over

dbSNP: rs587776693; hg19: chr19-13386663;