19-13230191-C-T

Position:

• chr19-13230191-C-T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_001127222.2(CACNA1A):​c.5419G>A​(p.Ala1807Thr) variant causes a missense change involving the alteration of a conserved nucleotide. 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: 31)
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7 U:1
• Conservation: PhyloP100: 7.82

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 17 ACMG points.

• PM1: In a repeat IV (size 263) in uniprot entity CAC1A_HUMAN there are 14 pathogenic changes around while only 1 benign (93%) 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). The gene has 137 curated pathogenic missense variants (we use a threshold of 10). The gene has 132 curated benign missense variants. GenCC has associacion of the 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, 0.95
• PP5: Variant 19-13230191-C-T is Pathogenic according to our data. Variant chr19-13230191-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 500851.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.5419G>A	p.Ala1807Thr	missense_variant	36/47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.5419G>A	p.Ala1807Thr	missense_variant	36/47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.5437G>A	p.Ala1813Thr	missense_variant	37/48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.5425G>A	p.Ala1809Thr	missense_variant	36/47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.5422G>A	p.Ala1808Thr	missense_variant	36/47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.5422G>A	p.Ala1808Thr	missense_variant	36/47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.5422G>A	p.Ala1808Thr	missense_variant	36/46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.5281G>A	p.Ala1761Thr	missense_variant	35/46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.5422G>A	p.Ala1808Thr	missense_variant	36/47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.5437G>A	p.Ala1813Thr	missense_variant	37/48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.5428G>A	p.Ala1810Thr	missense_variant	37/48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.5425G>A	p.Ala1809Thr	missense_variant	36/47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.5422G>A	p.Ala1808Thr	missense_variant	36/47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.5422G>A	p.Ala1808Thr	missense_variant	36/47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.5422G>A	p.Ala1808Thr	missense_variant	36/46	5		ENSP00000489777.1
CACNA1A	ENST00000636768.1	n.46G>A		non_coding_transcript_exon_variant	2/10	5		ENSP00000490190.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy, 42 Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 27, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	May 10, 2022	The CACNA1A c.5419G>A variant is classified as LIKELY PATHOGENIC (PS2, PM2, PP3) The CACNA1A c.5419G>A variant is a single nucleotide change in exon 36/47 of the CACNA1A gene, which is predicted to change the amino acid alanine at position 1807 in the protein to threonine. This variant has been identified as a de novo variant in this patient (PS2). This variant has been reported in dbSNP (rs1555736565) but is absent from population databases (PM2). This variant has been reported as a variant of uncertain significance in ClinVar by another diagnostic laboratory (ClinVar Variation ID: 500851). Computational predictions support a deleterious effect on the gene or gene product (PP3). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	Jul 12, 2023	- -

not provided Pathogenic:2 Uncertain:1

Uncertain significance, flagged submission	clinical testing	Eurofins Ntd Llc (ga)	Mar 20, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	CACNA1A: PM2, PS4:Moderate, PM6:Supporting, PP2, PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 12, 2024	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: 33278787, 34788679, 35722745, 35217970) -

Migraine, familial hemiplegic, 1;C4310716:Developmental and epileptic encephalopathy, 42 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Juno Genomics, Hangzhou Juno Genomics, Inc

-

PM2_Supporting+PP3_Strong+PS2_Moderate+PS4_Supporting+PP4+PP2 -

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 19, 2023

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1808 of the CACNA1A protein (p.Ala1808Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of CACNA1A-related conditions (PMID: 33278787, 35217970; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 500851). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	.;.;T;.;.;.;.;.;D;.;.;T;.;.;.;T;.;.
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D;D;D;D;D;D;D;D;D;D;.;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Pathogenic	4.4	.;.;.;.;H;.;.;.;.;.;.;.;.;.;H;.;.;.
PrimateAI	Pathogenic	0.94	D
PROVEAN	Uncertain	-4.0	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0010	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Pathogenic	0.0010	D;D;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.91
MutPred		0.80		.;.;Loss of catalytic residue at A1808 (P = 0.159);Loss of catalytic residue at A1808 (P = 0.159);Loss of catalytic residue at A1808 (P = 0.159);.;.;Loss of catalytic residue at A1808 (P = 0.159);.;.;.;Loss of catalytic residue at A1808 (P = 0.159);Loss of catalytic residue at A1808 (P = 0.159);.;Loss of catalytic residue at A1808 (P = 0.159);.;.;.;
MVP		0.97
MPC		2.1
ClinPred		1.0	D
GERP RS		4.3
Varity_R		0.63
gMVP		0.99

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: rs1555736565; hg19: chr19-13341005;