rs121909326

Variant names:

• chr19-13235219-A-G
• rs121909326
• NM_001127222.2:c.5123T>C

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1 PM2 PM5 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
• Publications: 6 publications found

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]

CACNA1A Gene-Disease associations (from GenCC):

• episodic ataxia type 2

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• undetermined early-onset epileptic encephalopathy

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, Illumina
• developmental and epileptic encephalopathy, 42

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• migraine, familial hemiplegic, 1

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• spinocerebellar ataxia type 6

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
• benign paroxysmal torticollis of infancy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial or sporadic hemiplegic migraine

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Lennox-Gastaut syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 16 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, 9 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 VariationId is 1470576.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 8510.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.5123T>C	p.Ile1708Thr	missense_variant	Exon 33 of 47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.5123T>C	p.Ile1708Thr	missense_variant	Exon 33 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.5141T>C	p.Ile1714Thr	missense_variant	Exon 34 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.5129T>C	p.Ile1710Thr	missense_variant	Exon 33 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.5126T>C	p.Ile1709Thr	missense_variant	Exon 33 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.5126T>C	p.Ile1709Thr	missense_variant	Exon 33 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.5126T>C	p.Ile1709Thr	missense_variant	Exon 33 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.4985T>C	p.Ile1662Thr	missense_variant	Exon 32 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.5126T>C	p.Ile1709Thr	missense_variant	Exon 33 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.5141T>C	p.Ile1714Thr	missense_variant	Exon 34 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.5132T>C	p.Ile1711Thr	missense_variant	Exon 34 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.5129T>C	p.Ile1710Thr	missense_variant	Exon 33 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.5126T>C	p.Ile1709Thr	missense_variant	Exon 33 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.5126T>C	p.Ile1709Thr	missense_variant	Exon 33 of 47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.5126T>C	p.Ile1709Thr	missense_variant	Exon 33 of 46	5		ENSP00000489777.1
CACNA1A	ENST00000636768.2	n.5126T>C		non_coding_transcript_exon_variant	Exon 33 of 45	5		ENSP00000490190.2
CACNA1A	ENST00000713789.1	n.*304T>C		non_coding_transcript_exon_variant	Exon 34 of 47			ENSP00000519091.1
CACNA1A	ENST00000713789.1	n.*304T>C		3_prime_UTR_variant	Exon 34 of 47			ENSP00000519091.1

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

African (AFR) AF: 0.00 AC: 0 AN: 33304

American (AMR) AF: 0.00 AC: 0 AN: 42752

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25964

East Asian (EAS) AF: 0.00 AC: 0 AN: 39438

South Asian (SAS) AF: 0.00 AC: 0 AN: 85208

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52942

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1108180

Other (OTH) AF: 0.00 AC: 0 AN: 60152

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Spinocerebellar ataxia type 6 Pathogenic:1

Sep 28, 2004

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Episodic ataxia type 2 Pathogenic:1

Nov 24, 2014

Mendelics

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

May 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). This variant is not present in population databases (gnomAD no frequency). 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 also known as 5404T>C or 5129T>C. ClinVar contains an entry for this variant (Variation ID: 8510). 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. -

Neurodevelopmental delay Pathogenic:1

-

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Pathogenic:1

May 11, 2018

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Feb 28, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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, 37422902, 39763636, 33057194, 36494636, 35982159, 34806130) -

Migraine, familial hemiplegic, 1 Pathogenic:1

Sep 28, 2004

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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
DEOGEN2	Pathogenic	0.95	.;D;T;.;.;.;.;.;D;.;.;T;.;.;.;T;.;.;.
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
MutationAssessor	Pathogenic	3.9	.;.;.;.;H;.;.;.;.;.;.;.;.;.;H;.;.;.;.
PhyloP100		9.3
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-4.5	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	.;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
Mutation Taster		=4/96	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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

Other links and lift over

dbSNP: rs121909326; hg19: chr19-13346033;