rs587776693

Variant names:

• chr19-13275849-C-A
• rs587776693
• NM_001127222.2:c.3989+1G>T

Your query was ambiguous. Multiple possible variants found:

• chr19-13275849-C-A
• chr19-13275849-C-G
• chr19-13275849-C-T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001127222.2(CACNA1A):​c.3989+1G>T 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 Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CACNA1A NM_001127222.2 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.80
• Publications: 0 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 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-A is Pathogenic according to our data. Variant chr19-13275849-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 1457947.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.3989+1G>T		splice_donor_variant, intron_variant	Intron 24 of 46	ENST00000360228.11	NP_001120694.1
CACNA1A	NM_001127221.2	c.3992+1G>T		splice_donor_variant, intron_variant	Intron 24 of 46	ENST00000638009.2	NP_001120693.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.3989+1G>T		splice_donor_variant, intron_variant	Intron 24 of 46	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638009.2	c.3992+1G>T		splice_donor_variant, intron_variant	Intron 24 of 46	1	NM_001127221.2	ENSP00000489913.1
CACNA1A	ENST00000638029.1	c.4001+1G>T		splice_donor_variant, intron_variant	Intron 24 of 47	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.3995+1G>T		splice_donor_variant, intron_variant	Intron 24 of 46	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.3992+1G>T		splice_donor_variant, intron_variant	Intron 24 of 46	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.3992+1G>T		splice_donor_variant, intron_variant	Intron 24 of 46	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.3992+1G>T		splice_donor_variant, intron_variant	Intron 24 of 45	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.3851+1G>T		splice_donor_variant, intron_variant	Intron 23 of 45	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.3992+1G>T		splice_donor_variant, intron_variant	Intron 24 of 46	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.4001+1G>T		splice_donor_variant, intron_variant	Intron 24 of 47	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.3992+1G>T		splice_donor_variant, intron_variant	Intron 24 of 47	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.3995+1G>T		splice_donor_variant, intron_variant	Intron 24 of 46	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.3992+1G>T		splice_donor_variant, intron_variant	Intron 24 of 46	5		ENSP00000490323.1
CACNA1A	ENST00000637276.1	c.3992+1G>T		splice_donor_variant, intron_variant	Intron 24 of 45	5		ENSP00000489777.1
CACNA1A	ENST00000636768.2	n.3992+1G>T		splice_donor_variant, intron_variant	Intron 24 of 44	5		ENSP00000490190.2
CACNA1A	ENST00000713789.1	n.3989+1G>T		splice_donor_variant, intron_variant	Intron 24 of 46			ENSP00000519091.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

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

Feb 10, 2022

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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Disruption of this splice site has been observed in individuals with episodic ataxia type 2 (PMID: 8898206, 22942164). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 24 of the CACNA1A gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CACNA1A are known to be pathogenic (PMID: 10371528, 19486177, 25735478, 27250579).

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	36
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0	.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.0	.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
MetaRNN	Benign	0.0	.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
MutationAssessor	Benign	0.0	.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
PhyloP100		7.8
PROVEAN	Benign	0.0	.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Benign	0.0
Sift	Pathogenic	0.0	.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Pathogenic	0.0	.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.0
GERP RS		4.6
Mutation Taster		=0/100	disease causing

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		0.76		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

Other links and lift over

dbSNP: rs587776693; hg19: chr19-13386663;