rs1555751762

Variant names:

• chr19-13283302-C-T
• rs1555751762
• NM_001127222.2:c.3787G>A

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_001127222.2(CACNA1A):​c.3787G>A​(p.Glu1263Lys) variant causes a missense 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• 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]

ACMG classification

Verdict is Pathogenic. Variant got 15 ACMG points.

• PM1: In a repeat III (size 283) in uniprot entity CAC1A_HUMAN there are 14 pathogenic changes around while only 1 benign (93%) in NM_001127222.2
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the CACNA1A gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 137 curated pathogenic missense variants (we use a threshold of 10). The gene has 132 curated benign missense variants. Gene score misZ: 5.7845 (above the threshold of 3.09). Trascript score misZ: 3.9354 (above the threshold of 3.09). GenCC associations: The gene is linked to 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.914
• PP5: Variant 19-13283302-C-T is Pathogenic according to our data. Variant chr19-13283302-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 542820.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.3787G>A	p.Glu1263Lys	missense_variant	Exon 22 of 47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.3787G>A	p.Glu1263Lys	missense_variant	Exon 22 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.3799G>A	p.Glu1267Lys	missense_variant	Exon 22 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.3793G>A	p.Glu1265Lys	missense_variant	Exon 22 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.3790G>A	p.Glu1264Lys	missense_variant	Exon 22 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.3790G>A	p.Glu1264Lys	missense_variant	Exon 22 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.3790G>A	p.Glu1264Lys	missense_variant	Exon 22 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.3649G>A	p.Glu1217Lys	missense_variant	Exon 21 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.3790G>A	p.Glu1264Lys	missense_variant	Exon 22 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.3799G>A	p.Glu1267Lys	missense_variant	Exon 22 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.3790G>A	p.Glu1264Lys	missense_variant	Exon 22 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.3793G>A	p.Glu1265Lys	missense_variant	Exon 22 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.3790G>A	p.Glu1264Lys	missense_variant	Exon 22 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.3790G>A	p.Glu1264Lys	missense_variant	Exon 22 of 47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.3790G>A	p.Glu1264Lys	missense_variant	Exon 22 of 46	5		ENSP00000489777.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Episodic ataxia type 2 Pathogenic:1

Jan 30, 2024

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Missense variant In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.92 (>=0.6, sensitivity 0.68 and specificity 0.92)]. Same nucleotide change resulting in same amino acid change has been previously reported to be associated with CACNA1A-related disorder (ClinVar ID: VCV000542820 /PMID: 28444220).The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 28444220, 33057194, 33233562, 35982159).The variant has been previously reported as assumed (i.e. paternity and maternity not confirmed) de novo in at least one similarly affected unrelated individual (PMID: 33233562 /3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

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

Mar 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1264 of the CACNA1A protein (p.Glu1264Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with CACNA1A-related disorders (PMID: 26633542, 28444220, 33233562; Invitae). In at least one individual the variant was observed to be de novo. This variant is also known as c.3787G>A:p.E1263K. ClinVar contains an entry for this variant (Variation ID: 542820). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CACNA1A protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Nov 28, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26633542, 33233562, 28444220) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.37	.;.;T;.;.;.;.;.;.;T;.;.;.;T;.
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D;D;D;D;.;D;D;D;D;D;D
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.0	.;.;.;.;M;.;.;.;.;.;.;.;M;.;.
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-4.0	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Pathogenic	0.0	D;D;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.88
MutPred		0.63		.;.;Gain of methylation at E1264 (P = 0.0082);Gain of methylation at E1264 (P = 0.0082);Gain of methylation at E1264 (P = 0.0082);.;Gain of methylation at E1264 (P = 0.0082);.;.;Gain of methylation at E1264 (P = 0.0082);Gain of methylation at E1264 (P = 0.0082);.;Gain of methylation at E1264 (P = 0.0082);.;Gain of methylation at E1264 (P = 0.0082);
MVP		0.98
MPC		2.4
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.89
gMVP		0.99

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555751762; hg19: chr19-13394116; COSMIC: COSV100801345;