chr19-13298766-C-T

Position:

• chr19-13298766-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2 BS2

The NM_001127222.2(CACNA1A):​c.2867G>A​(p.Arg956Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000395 in 1,520,648 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: 33)
  • Exomes 𝑓: 0.0000037 (0 hom.)
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 4.66

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 Likely_benign. Variant got -3 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CACNA1A. . Gene score misZ 5.7845 (greater than the threshold 3.09). Trascript score misZ 3.9354 (greater than threshold 3.09). GenCC has associacion of gene with 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.
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.2867G>A	p.Arg956Gln	missense_variant	19/47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.2867G>A	p.Arg956Gln	missense_variant	19/47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.2879G>A	p.Arg960Gln	missense_variant	19/48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.2873G>A	p.Arg958Gln	missense_variant	19/47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.2870G>A	p.Arg957Gln	missense_variant	19/47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.2870G>A	p.Arg957Gln	missense_variant	19/47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.2870G>A	p.Arg957Gln	missense_variant	19/46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.2729G>A	p.Arg910Gln	missense_variant	18/46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.2870G>A	p.Arg957Gln	missense_variant	19/47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.2879G>A	p.Arg960Gln	missense_variant	19/48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.2870G>A	p.Arg957Gln	missense_variant	19/48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.2873G>A	p.Arg958Gln	missense_variant	19/47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.2870G>A	p.Arg957Gln	missense_variant	19/47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.2870G>A	p.Arg957Gln	missense_variant	19/47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.2870G>A	p.Arg957Gln	missense_variant	19/46	5		ENSP00000489777.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152106 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000365 AC: 5 AN: 1368434 Hom.: 0 Cov.: 32 AF XY: 0.00000296 AC XY: 2 AN XY: 675954

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: 0.0000650

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: 152214 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74440

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 07, 2022

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. 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 not expected to disrupt CACNA1A protein function. ClinVar contains an entry for this variant (Variation ID: 387404). This variant has not been reported in the literature in individuals affected with CACNA1A-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 957 of the CACNA1A protein (p.Arg957Gln). -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 06, 2018

The p.R957Q variant (also known as c.2870G>A), located in coding exon 19 of the CACNA1A gene, results from a G to A substitution at nucleotide position 2870. The arginine at codon 957 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

May 04, 2018

A variant of uncertain significance has been identified in the CACNA1A gene. The R957Q variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R957Q variant was not observed in the Exome Aggregation Consortium (ExAC) data set, indicating it is not a common benign variant. The R957Q 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 position that is conserved across species. However, missense variants in nearby residues have not been reported in the Human Gene Mutation Database in association with CACNA1A-related disorders (Stenson et al., 2014). In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

Developmental and epileptic encephalopathy, 42 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

Feb 14, 2023

The missense c.2867G>A(p.Arg956Gln) variant in CACNA1A gene has not been reported previously as a pathogenic variant nor a benign variant, to our knowledge. The p.Arg956Gln variant is novel (not in any individuals) in gnomAD Exomes. This variant has been reported to the ClinVar database as Uncertain Significance. The amino acid change p.Arg956Gln in CACNA1A is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Arg at position 956 is changed to a Gln changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as a Variant of Uncertain Significance (VUS). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.062	.;.;T;.;.;.;.;.;.;T;.;.;.;T;.
Eigen	Benign	0.11
Eigen_PC	Benign	0.092
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D;D;D;.;D;D;D;D;D;D
M_CAP	Pathogenic	0.88	D
MetaRNN	Uncertain	0.53	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.56	D
MutationAssessor	Benign	1.7	.;.;.;.;L;.;.;.;.;.;.;.;L;.;.
PrimateAI	Pathogenic	0.93	D
PROVEAN	Uncertain	-2.5	.;N;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.50
Sift	Uncertain	0.021	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Uncertain	0.021	D;D;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.42
MutPred		0.21		.;.;Loss of MoRF binding (P = 0.0539);Loss of MoRF binding (P = 0.0539);Loss of MoRF binding (P = 0.0539);.;Loss of MoRF binding (P = 0.0539);.;.;Loss of MoRF binding (P = 0.0539);Loss of MoRF binding (P = 0.0539);.;Loss of MoRF binding (P = 0.0539);.;Loss of MoRF binding (P = 0.0539);
MVP		0.90
MPC		2.2
ClinPred		0.81	D
GERP RS		4.2
Varity_R		0.29
gMVP		0.70

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: rs551380805; hg19: chr19-13409580;