NM_001127222.2:c.2435G>A

Variant names:

• chr19-13299198-C-T
• rs953797733
• NM_001127222.2:c.2435G>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001127222.2(CACNA1A):​c.2435G>A​(p.Arg812Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000124 in 1,612,258 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.89

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the CACNA1A gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 137 curated pathogenic missense variants (we use a threshold of 10). The gene has 132 curated benign missense variants. Gene score misZ: 5.7845 (above the threshold of 3.09). Trascript score misZ: 3.9354 (above the threshold of 3.09). GenCC associations: The gene is linked to 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.2435G>A	p.Arg812Gln	missense_variant	Exon 19 of 47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.2435G>A	p.Arg812Gln	missense_variant	Exon 19 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.2447G>A	p.Arg816Gln	missense_variant	Exon 19 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.2441G>A	p.Arg814Gln	missense_variant	Exon 19 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.2438G>A	p.Arg813Gln	missense_variant	Exon 19 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.2438G>A	p.Arg813Gln	missense_variant	Exon 19 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.2438G>A	p.Arg813Gln	missense_variant	Exon 19 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.2297G>A	p.Arg766Gln	missense_variant	Exon 18 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.2438G>A	p.Arg813Gln	missense_variant	Exon 19 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.2447G>A	p.Arg816Gln	missense_variant	Exon 19 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.2438G>A	p.Arg813Gln	missense_variant	Exon 19 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.2441G>A	p.Arg814Gln	missense_variant	Exon 19 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.2438G>A	p.Arg813Gln	missense_variant	Exon 19 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.2438G>A	p.Arg813Gln	missense_variant	Exon 19 of 47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.2438G>A	p.Arg813Gln	missense_variant	Exon 19 of 46	5		ENSP00000489777.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152216 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460042 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726412

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 AF: 0.00000657 AC: 1 AN: 152216 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74362

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000312 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Jan 11, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 813 of the CACNA1A protein (p.Arg813Gln). This variant is present in population databases (no rsID available, gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CACNA1A-related conditions. ClinVar contains an entry for this variant (Variation ID: 387225). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt CACNA1A protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided Uncertain:1

Jun 27, 2016

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A variant of uncertain significance has been identified in the CACNA1A gene. The R813Q variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed in approximately 6,200 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R813Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a conserved position predicted to be within the cytoplasmic loop between the second and third homologous domains. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.060	.;.;T;.;.;.;.;.;.;T;.;.;.;T;.
Eigen	Uncertain	0.23
Eigen_PC	Benign	0.19
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
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.58	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.60	D
MutationAssessor	Benign	1.5	.;.;.;.;L;.;.;.;.;.;.;.;L;.;.
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-3.0	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.50
Sift	Benign	0.034	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.12	T;T;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.26
MutPred		0.27		.;.;Loss of MoRF binding (P = 0.0257);Loss of MoRF binding (P = 0.0257);Loss of MoRF binding (P = 0.0257);.;Loss of MoRF binding (P = 0.0257);.;.;Loss of MoRF binding (P = 0.0257);Loss of MoRF binding (P = 0.0257);.;Loss of MoRF binding (P = 0.0257);.;Loss of MoRF binding (P = 0.0257);
MVP		0.91
MPC		2.2
ClinPred		0.91	D
GERP RS		3.9
Varity_R		0.19
gMVP		0.91

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: rs953797733; hg19: chr19-13410012;