rs121908217

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PP2PP3_StrongPP5_Very_Strong

The NM_001127222.2(CACNA1A):c.1745G>A(p.Arg582Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,188 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 31)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

CACNA1A
NM_001127222.2 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:14O:2

Conservation

PhyloP100: 7.83

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 17 ACMG points.

PM1

In a transmembrane_region Helical; Name=S4 of repeat II (size 18) in uniprot entity CAC1A_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) 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, 0.982

PP5

Variant 19-13308452-C-T is Pathogenic according to our data. Variant chr19-13308452-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 8505.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-13308452-C-T is described in Lovd as [Pathogenic]. Variant chr19-13308452-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2 link	c.1745G>A	p.Arg582Gln	missense_variant	Exon 13 of 47	ENST00000360228.11	NP_001120694.1	O00555-8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CACNA1A	ENST00000360228.11 link	c.1745G>A	p.Arg582Gln	missense_variant	Exon 13 of 47	1	NM_001127222.2	ENSP00000353362.5	O00555-8
CACNA1A	ENST00000638029.1 link	c.1748G>A	p.Arg583Gln	missense_variant	Exon 13 of 48	5		ENSP00000489829.1	A0A087WW63
CACNA1A	ENST00000573710.7 link	c.1751G>A	p.Arg584Gln	missense_variant	Exon 13 of 47	5		ENSP00000460092.3	A0A1C7CYY9
CACNA1A	ENST00000635727.1 link	c.1748G>A	p.Arg583Gln	missense_variant	Exon 13 of 47	5		ENSP00000490001.1	A0A1B0GU81
CACNA1A	ENST00000637769.1 link	c.1748G>A	p.Arg583Gln	missense_variant	Exon 13 of 47	1		ENSP00000489778.1	A0A1B0GTN7
CACNA1A	ENST00000636012.1 link	c.1748G>A	p.Arg583Gln	missense_variant	Exon 13 of 46	5		ENSP00000490223.1	A0A1B0GUS3
CACNA1A	ENST00000637736.1 link	c.1607G>A	p.Arg536Gln	missense_variant	Exon 12 of 46	5		ENSP00000489861.1	A0A1B0GTW2
CACNA1A	ENST00000636389.1 link	c.1748G>A	p.Arg583Gln	missense_variant	Exon 13 of 47	5		ENSP00000489992.1	A0A1B0GU74
CACNA1A	ENST00000637432.1 link	c.1748G>A	p.Arg583Gln	missense_variant	Exon 13 of 48	5		ENSP00000490617.1	O00555-2
CACNA1A	ENST00000636549.1 link	c.1748G>A	p.Arg583Gln	missense_variant	Exon 13 of 48	5		ENSP00000490578.1	B5TYJ1
CACNA1A	ENST00000637927.1 link	c.1751G>A	p.Arg584Gln	missense_variant	Exon 13 of 47	5		ENSP00000489715.1	A0A1B0GTI4
CACNA1A	ENST00000635895.1 link	c.1748G>A	p.Arg583Gln	missense_variant	Exon 13 of 47	5		ENSP00000490323.1	A0A384DVW2
CACNA1A	ENST00000638009.2 link	c.1748G>A	p.Arg583Gln	missense_variant	Exon 13 of 47	1		ENSP00000489913.1	O00555-3
CACNA1A	ENST00000637276.1 link	c.1748G>A	p.Arg583Gln	missense_variant	Exon 13 of 46	5		ENSP00000489777.1	O00555-5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000402

AC:

AN:

248906

Hom.:

AF XY:

0.00000741

AC XY:

AN XY:

135040

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000886

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461188

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726860

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:6

Mar 26, 2020

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 19, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP1, PP2, PP3, PS3, PS4 -

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 22, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies show that the R583Q variant affects the voltage-gated calcium ion channel (Kraus et al., 2000); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 12707077, 12056940, 18056581, 19624685, 22527033, 30078120, 32888184, 30710491, 32626992, 10408534, 23407676, 11439943, 10734061, 28717674, 25969684, 24498617, 28900389, 33084218, 26814174, 35401678) -

Mar 30, 2023

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in individuals with familial hemiplegic migraine (FHM) and/or cerebellar ataxia (PMID: 24498617, 17142831, 11439943, 12707077). This variant segregates with disease in multiple families. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant leads to altered calcium channel function (PMID: 10734061). -

Aug 16, 2021

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Spinocerebellar ataxia type 6

Pathogenic:3

Jul 14, 2022

Genetics and Molecular Pathology, SA Pathology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 01, 2003

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jul 22, 2021

O&I group, Department of Genetics, University Medical Center of Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Migraine, familial hemiplegic, 1

Pathogenic:1Other:1

UniProtKB/Swiss-Prot

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Apr 01, 2003

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

Sep 01, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 583 of the CACNA1A protein (p.Arg583Gln). This variant is present in population databases (rs121908217, gnomAD 0.0009%). This missense change has been observed in individuals with CACNA1A-related conditions (PMID: 12707077, 20837964, 24498617, 26814174). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 8505). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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: 10734061). For these reasons, this variant has been classified as Pathogenic. -

Spinocerebellar ataxia type 6;C1720416:Episodic ataxia type 2;C1832884:Migraine, familial hemiplegic, 1;C4479236:Developmental and epileptic encephalopathy, 52

Pathogenic:1

Mar 20, 2022

Wendy Chung Laboratory, Columbia University Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Developmental and epileptic encephalopathy, 42

Pathogenic:1

Jun 01, 2022

Solve-RD Consortium

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: provider interpretation

Variant confirmed as disease-causing by referring clinical team -

Sporadic hemiplegic migraine

Pathogenic:1

Apr 01, 2003

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Familial hemiplegic migraine

Other:1

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.57

BayesDel_noAF

Pathogenic

0.58

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.25

.;.;T;.;.;.;.;.;.;T;.;.;.;T;.

Eigen

Pathogenic

0.97

Eigen_PC

Pathogenic

0.90

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

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

M_CAP

Pathogenic

0.86

MetaRNN

Pathogenic

0.98

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

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.9

.;.;.;.;H;.;.;H;.;.;.;.;H;.;.

PrimateAI

Pathogenic

0.82

PROVEAN

Uncertain

-3.8

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

REVEL

Pathogenic

0.96

Sift

Uncertain

0.0010

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

Sift4G

Uncertain

0.0020

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

Vest4

0.97

MutPred

0.91

Loss of MoRF binding (P = 0.0244);.;Loss of MoRF binding (P = 0.0244);Loss of MoRF binding (P = 0.0244);Loss of MoRF binding (P = 0.0244);.;Loss of MoRF binding (P = 0.0244);Loss of MoRF binding (P = 0.0244);Loss of MoRF binding (P = 0.0244);Loss of MoRF binding (P = 0.0244);Loss of MoRF binding (P = 0.0244);.;Loss of MoRF binding (P = 0.0244);.;Loss of MoRF binding (P = 0.0244);

MVP

1.0

MPC

2.4

ClinPred

1.0

GERP RS

5.4

Varity_R

0.63

gMVP

0.99

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over