NM_001127222.2:c.1745G>A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2PP3_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. 13/22 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

Publications

33 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:

ENSG00000306107 (HGNC:):

ENSG00000306107 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

PM2

Very rare variant in population databases, with high coverage;

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 VariationId is 8505.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.1745G>A	p.Arg582Gln	missense_variant	Exon 13 of 47	ENST00000360228.11	NP_001120694.1
CACNA1A	NM_001127221.2 link	c.1748G>A	p.Arg583Gln	missense_variant	Exon 13 of 47	ENST00000638009.2	NP_001120693.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CACNA1A	ENST00000360228.11 link	c.1745G>A	p.Arg582Gln	missense_variant	Exon 13 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638009.2 link	c.1748G>A	p.Arg583Gln	missense_variant	Exon 13 of 47	1	NM_001127221.2	ENSP00000489913.1
CACNA1A	ENST00000638029.1 link	c.1748G>A	p.Arg583Gln	missense_variant	Exon 13 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7 link	c.1751G>A	p.Arg584Gln	missense_variant	Exon 13 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1 link	c.1748G>A	p.Arg583Gln	missense_variant	Exon 13 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1 link	c.1748G>A	p.Arg583Gln	missense_variant	Exon 13 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1 link	c.1748G>A	p.Arg583Gln	missense_variant	Exon 13 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1 link	c.1607G>A	p.Arg536Gln	missense_variant	Exon 12 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1 link	c.1748G>A	p.Arg583Gln	missense_variant	Exon 13 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1 link	c.1748G>A	p.Arg583Gln	missense_variant	Exon 13 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1 link	c.1748G>A	p.Arg583Gln	missense_variant	Exon 13 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1 link	c.1751G>A	p.Arg584Gln	missense_variant	Exon 13 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1 link	c.1748G>A	p.Arg583Gln	missense_variant	Exon 13 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000637276.1 link	c.1748G>A	p.Arg583Gln	missense_variant	Exon 13 of 46	5		ENSP00000489777.1
CACNA1A	ENST00000636768.2 link	n.1748G>A		non_coding_transcript_exon_variant	Exon 13 of 45	5		ENSP00000490190.2
CACNA1A	ENST00000713789.1 link	n.1745G>A		non_coding_transcript_exon_variant	Exon 13 of 47			ENSP00000519091.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000402

AC:

AN:

248906

AF XY:

0.00000741

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 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

African (AFR)

AF:

0.00

AC:

AN:

33472

American (AMR)

AF:

0.00

AC:

AN:

44684

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26114

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.00

AC:

AN:

86152

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53388

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5748

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111574

Other (OTH)

AF:

0.00

AC:

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:6

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 26, 2020

Genetic Services Laboratory, University of Chicago

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) -

Aug 16, 2021

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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). -

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 -

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

Apr 01, 2003

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;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, Boston Children's Hospital

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

(source)

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;.;.

PhyloP100

7.8

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

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over