rs121908217

Positions:

chr19-13308452-C-T

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 gene, where missense usually causes diseases (based on misZ statistic), CACNA1A. . Gene score misZ 5.7845 (greater than the threshold 3.09). Trascript score misZ 3.9354 (greater than threshold 3.09). GenCC has associacion of gene with 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/exons	MANE	Protein	UniProt
CACNA1A	NM_001127222.2 linkuse as main transcript	c.1745G>A	p.Arg582Gln	missense_variant	13/47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11 linkuse as main transcript	c.1745G>A	p.Arg582Gln	missense_variant	13/47	1	NM_001127222.2	ENSP00000353362		O00555-8

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

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 19, 2023	PP1, PP2, PP3, PS3, PS4 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 22, 2023	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 30, 2023	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). -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 16, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 26, 2020	- -

Spinocerebellar ataxia type 6

Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2003	- -
Pathogenic, no assertion criteria provided	research	O&I group, Department of Genetics, University Medical Center of Groningen	Jul 22, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Jul 14, 2022	- -

Migraine, familial hemiplegic, 1

Pathogenic:1Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2003	- -
not provided, no classification provided	literature only	UniProtKB/Swiss-Prot	-	- -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 12, 2022

ClinVar contains an entry for this variant (Variation ID: 8505). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects CACNA1A function (PMID: 10734061). 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. 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. This variant is present in population databases (rs121908217, gnomAD 0.0009%). 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). -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Wendy Chung Laboratory, Columbia University Medical Center

Mar 20, 2022

- -

Developmental and epileptic encephalopathy, 42

Pathogenic:1

Likely pathogenic, no assertion criteria provided

provider interpretation

Solve-RD Consortium

Jun 01, 2022

Variant confirmed as disease-causing by referring clinical team -

Sporadic hemiplegic migraine

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 01, 2003

- -

Familial hemiplegic migraine

Other:1

not provided, no classification provided

literature only

GeneReviews

- -

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;.;.

MutationTaster

Benign

1.0

A;A;A

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