rs121909326

chr19-13235219-A-G

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_001127222.2(CACNA1A):c.5123T>C(p.Ile1708Thr) 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I1708L) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 9.27

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 hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 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 chr19-13235220-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1470576.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, 0.934
• PP5: Variant 19-13235219-A-G is Pathogenic according to our data. Variant chr19-13235219-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 8510.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-13235219-A-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1A	NM_001127222.2	c.5123T>C	p.Ile1708Thr	missense_variant	33/47	ENST00000360228.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1A	ENST00000360228.11	c.5123T>C	p.Ile1708Thr	missense_variant	33/47	1	NM_001127222.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1453706 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 722492

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

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.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Episodic ataxia type 2 Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Mendelics

Nov 24, 2014

- -

Spinocerebellar ataxia type 6 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 28, 2004

- -

Neurodevelopmental delay Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

-

- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 18, 2022

ClinVar contains an entry for this variant (Variation ID: 8510). This variant is also known as 5404T>C or 5129T>C. This missense change has been observed in individual(s) with familial hemiplegic migraine (PMID: 15240985, 15452324). In at least one individual the variant was observed to be de novo. 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 isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1709 of the CACNA1A protein (p.Ile1709Thr). 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. For these reasons, this variant has been classified as Pathogenic. -

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 11, 2018

The p.I1709T variant (also known as c.5126T>C), located in coding exon 33 of the CACNA1A gene, results from a T to C substitution at nucleotide position 5126. The isoleucine at codon 1709 is replaced by threonine, an amino acid with similar properties. This variant (designated as I1710T) occurred de novo in a proband with slowly progressive cerebellar ataxia, cerebellar atrophy, and hemiplegic migraine attacks. This proband's two children both have cerebellar ataxia, cerebellar atrophy, migraine without aura, two episodes of hemiplegic migraine, and a history of childhood seizures (Kors EE et al. Neurology, 2004 Sep;63:1136-7). This variant also occurred de novo in a 14-year-old female with right hemiplegia, aphasia, and altered consciousness followed by recurrent and prolonged right unilateral seizures after a head trauma; she had two additional attacks of headaches with comas, hemiplegia, and status epilepticus, moderate ataxia between episodes, a normal brain MRI, and an abnormal EEG (Riant F et al. Neurology, 2010 Sep;75:967-72; Beauvais K et al. Eur. Neurol., 2004 Jul;52:58-61). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 23, 2022

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 20837964, 15452324, 28717674, 15240985) -

Migraine, familial hemiplegic, 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 28, 2004

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
Cadd	Uncertain	25
Dann	Uncertain	1.0
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;.;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.93	D;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	0.89	D
Sift4G	Pathogenic	0.0010	D;D;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.82
MutPred		0.69		.;.;Loss of stability (P = 0.0463);Loss of stability (P = 0.0463);Loss of stability (P = 0.0463);.;.;Loss of stability (P = 0.0463);.;.;.;Loss of stability (P = 0.0463);Loss of stability (P = 0.0463);.;Loss of stability (P = 0.0463);.;.;.;.;
MVP		1.0
MPC		1.5
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.77
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: rs121909326; hg19: chr19-13346033;