19-13303584-C-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1PM2PP2PP3_ModeratePP5_Very_Strong

The NM_001127222.2(CACNA1A):​c.2134G>A​(p.Ala712Thr) variant causes a missense change. 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: 29)

Consequence

CACNA1A
NM_001127222.2 missense

Scores

14
3
2

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12O:1

Conservation

PhyloP100: 6.16
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 15 ACMG points.

PM1
In a transmembrane_region Helical; Name=S6 of repeat II (size 24) 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, 0.883
PP5
Variant 19-13303584-C-T is Pathogenic according to our data. Variant chr19-13303584-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 254268.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-13303584-C-T is described in UniProt as null. Variant chr19-13303584-C-T is described in UniProt as null. Variant chr19-13303584-C-T is described in UniProt as null. Variant chr19-13303584-C-T is described in UniProt as null. Variant chr19-13303584-C-T is described in UniProt as null. Variant chr19-13303584-C-T is described in UniProt as null. Variant chr19-13303584-C-T is described in UniProt as null. Variant chr19-13303584-C-T is described in UniProt as null. Variant chr19-13303584-C-T is described in UniProt as null. Variant chr19-13303584-C-T is described in UniProt as null. Variant chr19-13303584-C-T is described in UniProt as null. Variant chr19-13303584-C-T is described in UniProt as null. Variant chr19-13303584-C-T is described in UniProt as null. Variant chr19-13303584-C-T is described in UniProt as null. Variant chr19-13303584-C-T is described in UniProt as null. Variant chr19-13303584-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CACNA1ANM_001127222.2 linkc.2134G>A p.Ala712Thr missense_variant Exon 17 of 47 ENST00000360228.11 NP_001120694.1 O00555-8

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CACNA1AENST00000360228.11 linkc.2134G>A p.Ala712Thr missense_variant Exon 17 of 47 1 NM_001127222.2 ENSP00000353362.5 O00555-8
CACNA1AENST00000638029.1 linkc.2137G>A p.Ala713Thr missense_variant Exon 17 of 48 5 ENSP00000489829.1 A0A087WW63
CACNA1AENST00000573710.7 linkc.2140G>A p.Ala714Thr missense_variant Exon 17 of 47 5 ENSP00000460092.3 A0A1C7CYY9
CACNA1AENST00000635727.1 linkc.2137G>A p.Ala713Thr missense_variant Exon 17 of 47 5 ENSP00000490001.1 A0A1B0GU81
CACNA1AENST00000637769.1 linkc.2137G>A p.Ala713Thr missense_variant Exon 17 of 47 1 ENSP00000489778.1 A0A1B0GTN7
CACNA1AENST00000636012.1 linkc.2137G>A p.Ala713Thr missense_variant Exon 17 of 46 5 ENSP00000490223.1 A0A1B0GUS3
CACNA1AENST00000637736.1 linkc.1996G>A p.Ala666Thr missense_variant Exon 16 of 46 5 ENSP00000489861.1 A0A1B0GTW2
CACNA1AENST00000636389.1 linkc.2137G>A p.Ala713Thr missense_variant Exon 17 of 47 5 ENSP00000489992.1 A0A1B0GU74
CACNA1AENST00000637432.1 linkc.2137G>A p.Ala713Thr missense_variant Exon 17 of 48 5 ENSP00000490617.1 O00555-2
CACNA1AENST00000636549.1 linkc.2137G>A p.Ala713Thr missense_variant Exon 17 of 48 5 ENSP00000490578.1 B5TYJ1
CACNA1AENST00000637927.1 linkc.2140G>A p.Ala714Thr missense_variant Exon 17 of 47 5 ENSP00000489715.1 A0A1B0GTI4
CACNA1AENST00000635895.1 linkc.2137G>A p.Ala713Thr missense_variant Exon 17 of 47 5 ENSP00000490323.1 A0A384DVW2
CACNA1AENST00000638009.2 linkc.2137G>A p.Ala713Thr missense_variant Exon 17 of 47 1 ENSP00000489913.1 O00555-3
CACNA1AENST00000637276.1 linkc.2137G>A p.Ala713Thr missense_variant Exon 17 of 46 5 ENSP00000489777.1 O00555-5

Frequencies

GnomAD3 genomes
Cov.:
29
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
29

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:12Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy, 42 Pathogenic:6
May 31, 2022
Cytoplasmic Inheritance Laboratory, Institute of Genetics and Cytology
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

We consider the variant NM_001127221.2:c.2137G>A as disease-causing; it results in an amino acid substitution p.Ala713Thr. -

Sep 12, 2013
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Jan 30, 2023
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

A heterozygous missense variation in exon 17 of the CACNA1A gene that results in the amino acid substitution of Threonine for Alanine at codon 712 (p.Ala712Thr) was detected. This variant has not been reported in the 1000 genomes and gnomAD databases. The in silico predictions of the variant are probably damaging by PolyPhen-2 (HumDiv) and damaging by SIFT, LRT and MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as a Likely Pathogenic. -

Sep 01, 2022
3billion
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.95; 3Cnet: 0.75). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000254268). A different missense change at the same codon (p.Ala712Ser) has been reported to be associated with CACNA1A -related disorder (ClinVar ID: VCV000997449). However the evidence of pathogenicity is insufficient at this time. Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -

Dec 04, 2019
Illumina Laboratory Services, Illumina
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The CACNA1A c.2137G>A (p.Ala713Thr) variant is a missense variant that has been reported in a heterozygous, de novo state in at least three unrelated individuals with epilepsy syndromes (Epi4K Consortium, Epilepsy Phenome/Genome Project 2013; Epi4K Consortium 2016; Balck et al. 2017). It was also identified in a fourth individual with seizures who had a similarly affected sibling. In this case, the variant was inherited from an unaffected parent who was mosaic for the variant with 6% mutational load in lymphocyte-derived DNA (Balck et al. 2017). In addition to early onset of multiple seizure types, individuals with this variant also showed abnormal movements in utero, ataxic movements and gait, mild dysmetria, dystonic posturing, and developmental delay/intellectual disability. The p.Ala713Thr variant is not found in the Genome Aggregation Database in a region of good sequencing coverage. Based on the collective evidence, the p.Ala713Thr variant is classified as pathogenic for early infantile epileptic encephalopathy. -

Jul 23, 2018
Génétique des Maladies du Développement, Hospices Civils de Lyon
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Episodic ataxia type 2;C4310716:Developmental and epileptic encephalopathy, 42 Pathogenic:1
Sep 30, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 713 of the CACNA1A protein (p.Ala713Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with epileptic encephalopathy (PMID: 23934111, 29186148). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 254268). 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%. For these reasons, this variant has been classified as Pathogenic. -

Inborn genetic diseases Pathogenic:1
Aug 05, 2015
Ambry Genetics
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Abnormality of the nervous system Pathogenic:1
Jul 10, 2021
Kariminejad - Najmabadi Pathology & Genetics Center
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Pathogenic:1
Jan 21, 2022
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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: 27476654, 29186148, 23934111, 28488083, 26633542, 28455667, 31175295, 33425808, 29100083, 31468518, 32005694, 34102571, 34263451) -

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: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Spinocerebellar ataxia type 6;C1720416:Episodic ataxia type 2;C1832884:Migraine, familial hemiplegic, 1;C4310716:Developmental and epileptic encephalopathy, 42 Pathogenic:1
Sep 18, 2021
Fulgent Genetics, Fulgent Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Familial hemiplegic migraine;C1720416:Episodic ataxia type 2;C4310716:Developmental and epileptic encephalopathy, 42 Other:1
-
GenomeConnect - Brain Gene Registry
Significance: not provided
Review Status: no classification provided
Collection Method: phenotyping only

Variant interpreted as Likely pathogenic and reported on 08-12-2015 by lab or GTR ID 61756. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IIDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator John Constantino MD PhD from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.90
BayesDel_addAF
Pathogenic
0.37
D
BayesDel_noAF
Pathogenic
0.30
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Benign
0.23
.;.;T;.;.;.;.;.;.;T;.;.;.;T;.
Eigen
Pathogenic
0.90
Eigen_PC
Pathogenic
0.83
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Pathogenic
0.99
D;D;D;D;D;D;D;D;.;D;D;D;D;D;D
M_CAP
Pathogenic
0.78
D
MetaRNN
Pathogenic
0.88
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.6
.;.;.;.;H;.;.;H;.;.;.;.;H;.;.
PrimateAI
Pathogenic
0.93
D
PROVEAN
Uncertain
-3.7
.;D;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL
Pathogenic
0.95
Sift
Uncertain
0.0040
.;D;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G
Pathogenic
0.0010
D;D;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4
0.86
MutPred
0.46
Gain of glycosylation at A713 (P = 0.0905);.;Gain of glycosylation at A713 (P = 0.0905);Gain of glycosylation at A713 (P = 0.0905);Gain of glycosylation at A713 (P = 0.0905);.;Gain of glycosylation at A713 (P = 0.0905);Gain of glycosylation at A713 (P = 0.0905);Gain of glycosylation at A713 (P = 0.0905);Gain of glycosylation at A713 (P = 0.0905);Gain of glycosylation at A713 (P = 0.0905);.;Gain of glycosylation at A713 (P = 0.0905);.;Gain of glycosylation at A713 (P = 0.0905);
MVP
0.94
MPC
2.2
ClinPred
1.0
D
GERP RS
5.0
Varity_R
0.50
gMVP
0.97

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

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

Other links and lift over

dbSNP: rs886037945; hg19: chr19-13414398; COSMIC: COSV64197352; COSMIC: COSV64197352; API