rs121908214

chr19-13230185-T-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Moderate

The NM_001127222.2(CACNA1A):c.5425A>C(p.Ile1809Leu) 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 Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I1809T) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2 O:2
• Conservation: PhyloP100: 7.93

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 11 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 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 chr19-13230184-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1019797.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant where missense usually causes diseases, CACNA1A
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.903
• PP5: Variant 19-13230185-T-G is Pathogenic according to our data. Variant chr19-13230185-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 8490.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-13230185-T-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1A	NM_001127222.2	c.5425A>C	p.Ile1809Leu	missense_variant	36/47	ENST00000360228.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1A	ENST00000360228.11	c.5425A>C	p.Ile1809Leu	missense_variant	36/47	1	NM_001127222.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:2

Revision: criteria provided, single submitter

Submissions by phenotype

Migraine, familial hemiplegic, 1 Pathogenic:1 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 1996	- -
not provided, no classification provided	literature only	UniProtKB/Swiss-Prot	-	- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jun 06, 2020

For these reasons, this variant has been classified as Pathogenic. This variant has been reported to affect CACNA1A protein function (PMID: 10024348, 9488686, 12235360). This variant has been observed in individual(s) with familial hemiplegic migraine (PMID: 8898206). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 8490). This variant is not present in population databases (ExAC no frequency). This sequence change replaces isoleucine with leucine at codon 1810 of the CACNA1A protein (p.Ile1810Leu). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and leucine. -

Familial hemiplegic migraine Other:1

not provided, no classification provided

literature only

GeneReviews

-

Hemiplegic attacks plus ataxia -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
Cadd	Pathogenic	29
Dann	Uncertain	0.99
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;.;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	0.90	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Pathogenic	0.93	D
Sift4G	Pathogenic	0.0	D;D;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.82
MutPred		0.68		.;.;Loss of catalytic residue at D1812 (P = 0.2729);Loss of catalytic residue at D1812 (P = 0.2729);Loss of catalytic residue at D1812 (P = 0.2729);.;.;Loss of catalytic residue at D1812 (P = 0.2729);.;.;.;Loss of catalytic residue at D1812 (P = 0.2729);Loss of catalytic residue at D1812 (P = 0.2729);.;Loss of catalytic residue at D1812 (P = 0.2729);.;.;.;
MVP		0.98
MPC		1.3
ClinPred		0.92	D
GERP RS		4.3
Varity_R		0.60
gMVP		0.96

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: rs121908214; hg19: chr19-13340999;