19-13359680-C-T

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_001127222.2(CACNA1A):c.904G>A(p.Asp302Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,455,160 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D302G) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 7.79

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 19 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_001127222.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-13359679-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1019492.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.
• PP2: Missense variant where missense usually causes diseases, CACNA1A
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.941
• PP5: Variant 19-13359680-C-T is Pathogenic according to our data. Variant chr19-13359680-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 216896.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-13359680-C-T is described in Lovd as [Pathogenic]. Variant chr19-13359680-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1A	NM_001127222.2	c.904G>A	p.Asp302Asn	missense_variant	6/47	ENST00000360228.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1A	ENST00000360228.11	c.904G>A	p.Asp302Asn	missense_variant	6/47	1	NM_001127222.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1455160 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 723064

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2022	CACNA1A: PM2, PP4:Moderate, PS4:Moderate, PP2, PP3 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratoire de Génétique Moléculaire, CHU Bordeaux	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 01, 2022	Not observed at significant frequency in large population cohorts (gnomAD); Reported in ClinVar but additional evidence is not available (ClinVar Variant ID# 216896); This variant is associated with the following publications: (PMID: 27066515, 25326637, 27871455, 24486772) -

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Sep 07, 2022

For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 216896). This missense change has been observed in individuals with episodic ataxia 2 (PMID: 24486772, 25326637, 27066515, 27871455). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 302 of the CACNA1A protein (p.Asp302Asn). -

Spinocerebellar ataxia type 6;C1720416:Episodic ataxia type 2 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

UCLA Clinical Genomics Center, UCLA

Sep 09, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
Cadd	Pathogenic	32
Dann	Uncertain	1.0
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.85
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	0.88	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.86	D
Sift4G	Uncertain	0.0040	D;D;.;.;.;.;.;.;.;.;.;D;.;.;.
Polyphen		1.0	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.98
MutPred		0.77		Gain of glycosylation at T299 (P = 0.0735);Gain of glycosylation at T299 (P = 0.0735);Gain of glycosylation at T299 (P = 0.0735);Gain of glycosylation at T299 (P = 0.0735);Gain of glycosylation at T299 (P = 0.0735);.;Gain of glycosylation at T299 (P = 0.0735);Gain of glycosylation at T299 (P = 0.0735);Gain of glycosylation at T299 (P = 0.0735);Gain of glycosylation at T299 (P = 0.0735);Gain of glycosylation at T299 (P = 0.0735);Gain of glycosylation at T299 (P = 0.0735);Gain of glycosylation at T299 (P = 0.0735);Gain of glycosylation at T299 (P = 0.0735);Gain of glycosylation at T299 (P = 0.0735);
MVP		0.97
MPC		2.2
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.68
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: rs863224852; hg19: chr19-13470494; COSMIC: COSV105922369; COSMIC: COSV105922369;