19-13303584-C-T

Position:

• chr19-13303584-C-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12 O:1
• Conservation: PhyloP100: 6.16

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]

ACMG classification

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 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, 0.883
• 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/exons	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.2134G>A	p.Ala712Thr	missense_variant	17/47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.2134G>A	p.Ala712Thr	missense_variant	17/47	1	NM_001127222.2	ENSP00000353362

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 29

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy, 42 Pathogenic:6

Likely pathogenic, criteria provided, single submitter	clinical testing	3billion	Sep 01, 2022	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Génétique des Maladies du Développement, Hospices Civils de Lyon	Jul 23, 2018	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 12, 2013	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	Jan 30, 2023	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. -
Likely pathogenic, no assertion criteria provided	clinical testing	Cytoplasmic Inheritance Laboratory, Institute of Genetics and Cytology	May 31, 2022	We consider the variant NM_001127221.2:c.2137G>A as disease-causing; it results in an amino acid substitution p.Ala713Thr. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Dec 04, 2019	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. -

Episodic ataxia type 2;C4310716:Developmental and epileptic encephalopathy, 42 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 13, 2022

ClinVar contains an entry for this variant (Variation ID: 254268). 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. This variant is not present in population databases (gnomAD no frequency). 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). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. -

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 05, 2015

- -

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Wendy Chung Laboratory, Columbia University Medical Center

Mar 20, 2022

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 21, 2022

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) -

Abnormality of the nervous system Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Kariminejad - Najmabadi Pathology & Genetics Center

Jul 10, 2021

- -

Spinocerebellar ataxia type 6;C1720416:Episodic ataxia type 2;C1832884:Migraine, familial hemiplegic, 1;C4310716:Developmental and epileptic encephalopathy, 42 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 18, 2021

- -

Familial hemiplegic migraine;C1720416:Episodic ataxia type 2;C4310716:Developmental and epileptic encephalopathy, 42 Other:1

not provided, no classification provided

phenotyping only

GenomeConnect - Brain Gene Registry

-

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;.;.
MutationTaster	Benign	1.0	D;D;D
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

Other links and lift over

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