rs121908215

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong

The NM_001127222.2(CACNA1A):c.877G>A(p.Gly293Arg) 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. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Consequence

CACNA1A
NM_001127222.2 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4O:1

Conservation

PhyloP100: 7.79

Publications

9 publications found

Variant links:

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

CACNA1A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 14 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_001127222.2

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.911

PP5

Variant 19-13359707-C-T is Pathogenic according to our data. Variant chr19-13359707-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 8496.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 link	c.877G>A	p.Gly293Arg	missense_variant	Exon 6 of 47	ENST00000360228.11	NP_001120694.1
CACNA1A	NM_001127221.2 link	c.877G>A	p.Gly293Arg	missense_variant	Exon 6 of 47	ENST00000638009.2	NP_001120693.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CACNA1A	ENST00000360228.11 link	c.877G>A	p.Gly293Arg	missense_variant	Exon 6 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638009.2 link	c.877G>A	p.Gly293Arg	missense_variant	Exon 6 of 47	1	NM_001127221.2	ENSP00000489913.1
CACNA1A	ENST00000638029.1 link	c.877G>A	p.Gly293Arg	missense_variant	Exon 6 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7 link	c.877G>A	p.Gly293Arg	missense_variant	Exon 6 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1 link	c.877G>A	p.Gly293Arg	missense_variant	Exon 6 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1 link	c.877G>A	p.Gly293Arg	missense_variant	Exon 6 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1 link	c.877G>A	p.Gly293Arg	missense_variant	Exon 6 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1 link	c.736G>A	p.Gly246Arg	missense_variant	Exon 5 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1 link	c.877G>A	p.Gly293Arg	missense_variant	Exon 6 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1 link	c.877G>A	p.Gly293Arg	missense_variant	Exon 6 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1 link	c.877G>A	p.Gly293Arg	missense_variant	Exon 6 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1 link	c.877G>A	p.Gly293Arg	missense_variant	Exon 6 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1 link	c.877G>A	p.Gly293Arg	missense_variant	Exon 6 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000637276.1 link	c.877G>A	p.Gly293Arg	missense_variant	Exon 6 of 46	5		ENSP00000489777.1
CACNA1A	ENST00000636768.2 link	n.877G>A		non_coding_transcript_exon_variant	Exon 6 of 45	5		ENSP00000490190.2
CACNA1A	ENST00000713789.1 link	n.877G>A		non_coding_transcript_exon_variant	Exon 6 of 47			ENSP00000519091.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Spinocerebellar ataxia type 6

Pathogenic:1Other:1

Jun 28, 2005

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

UniProtKB/Swiss-Prot

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Episodic ataxia type 2

Pathogenic:1

Jun 28, 2005

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

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

Pathogenic:1

Jun 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 293 of the CACNA1A protein (p.Gly293Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of episodic ataxia type 2 (PMID: 9345107; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 8496). 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%. Experimental studies have shown that this missense change affects CACNA1A function (PMID: 11742003, 15985579, 18434528). For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:1

Jan 30, 2024

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate altered channel function (PMID: 15985579); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 11742003, 11179022, 16325861, 18602318, 32899500, 12707077, 32116539, 9345107, 15985579) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.53

BayesDel_noAF

Pathogenic

0.53

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.95

.;D;T;.;.;.;.;.;.;T;.;.;.;T;.

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

D;D;D;D;D;D;D;D;.;D;D;D;D;D;D

M_CAP

Pathogenic

0.94

MetaRNN

Pathogenic

0.91

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.8

.;M;.;.;M;.;.;M;.;.;.;.;M;.;.

PhyloP100

7.8

PrimateAI

Pathogenic

0.82

PROVEAN

Pathogenic

-6.7

.;D;.;.;.;.;.;.;.;.;.;.;.;.;.

REVEL

Pathogenic

0.92

Sift

Benign

0.047

.;D;.;.;.;.;.;.;.;.;.;.;.;.;.

Sift4G

Pathogenic

0.0

D;D;.;.;.;.;.;.;.;.;.;D;.;.;.

Polyphen

1.0

.;D;.;.;.;.;.;.;.;.;.;.;.;.;.

Vest4

0.95

MutPred

0.56

Loss of catalytic residue at P289 (P = 0.0966);Loss of catalytic residue at P289 (P = 0.0966);Loss of catalytic residue at P289 (P = 0.0966);Loss of catalytic residue at P289 (P = 0.0966);Loss of catalytic residue at P289 (P = 0.0966);.;Loss of catalytic residue at P289 (P = 0.0966);Loss of catalytic residue at P289 (P = 0.0966);Loss of catalytic residue at P289 (P = 0.0966);Loss of catalytic residue at P289 (P = 0.0966);Loss of catalytic residue at P289 (P = 0.0966);Loss of catalytic residue at P289 (P = 0.0966);Loss of catalytic residue at P289 (P = 0.0966);Loss of catalytic residue at P289 (P = 0.0966);Loss of catalytic residue at P289 (P = 0.0966);

MVP

0.98

MPC

2.5

ClinPred

1.0

GERP RS

5.4

Varity_R

0.77

gMVP

0.97

Mutation Taster

=4/96

disease causing (ClinVar)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over