19-13298709-C-T

Position:

• chr19-13298709-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_001127222.2(CACNA1A):​c.2924G>A​(p.Arg975Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,466,380 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.76

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.33386835).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.2924G>A	p.Arg975Gln	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.2924G>A	p.Arg975Gln	missense_variant	19/47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.2936G>A	p.Arg979Gln	missense_variant	19/48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.2930G>A	p.Arg977Gln	missense_variant	19/47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.2927G>A	p.Arg976Gln	missense_variant	19/47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.2927G>A	p.Arg976Gln	missense_variant	19/47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.2927G>A	p.Arg976Gln	missense_variant	19/46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.2786G>A	p.Arg929Gln	missense_variant	18/46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.2927G>A	p.Arg976Gln	missense_variant	19/47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.2936G>A	p.Arg979Gln	missense_variant	19/48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.2927G>A	p.Arg976Gln	missense_variant	19/48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.2930G>A	p.Arg977Gln	missense_variant	19/47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.2927G>A	p.Arg976Gln	missense_variant	19/47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.2927G>A	p.Arg976Gln	missense_variant	19/47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.2927G>A	p.Arg976Gln	missense_variant	19/46	5		ENSP00000489777.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151896 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000242

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: 0.00000152 AC: 2 AN: 1314484 Hom.: 0 Cov.: 32 AF XY: 0.00000309 AC XY: 2 AN XY: 648018

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: 0.00000191

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151896 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74194

Gnomad4 AFR AF: 0.0000242

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

Bravo AF: 0.00000756

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 11, 2019

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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with CACNA1A-related disease. While this variant is not present in population databases, the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This sequence change replaces arginine with glutamine at codon 976 of the CACNA1A protein (p.Arg976Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. -

Developmental and epileptic encephalopathy, 42 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Oct 28, 2019

The CACNA1A c.2927G>A (p.Arg976Gln) variant is a missense variant. A literature search was performed for the gene, cDNA change, and amino acid change. No publications were found based on this search. This variant is not found in the Genome Aggregation Database in a region of good sequence coverage, so the variant is presumed to be rare. Based on the limited evidence, the p.Arg976Gln is classified as a variant of unknown significance for early infantile epileptic encephalopathy. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.032	.;.;T;.;.;.;.;.;.;T;.;.;.;T;.
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.63	D
LIST_S2	Uncertain	0.91	D;D;D;D;D;D;D;D;.;D;D;D;D;D;D
M_CAP	Pathogenic	0.96	D
MetaRNN	Benign	0.33	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.25	D
MutationAssessor	Benign	1.6	.;.;.;.;L;.;.;.;.;.;.;.;L;.;.
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-1.9	.;N;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Benign	0.27
Sift	Benign	0.033	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.070	T;T;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.18
MutPred		0.24		.;.;Loss of loop (P = 0.0374);Loss of loop (P = 0.0374);Loss of loop (P = 0.0374);.;Loss of loop (P = 0.0374);.;.;Loss of loop (P = 0.0374);Loss of loop (P = 0.0374);.;Loss of loop (P = 0.0374);.;Loss of loop (P = 0.0374);
MVP		0.85
MPC		1.7
ClinPred		0.45	T
GERP RS		4.1
Varity_R		0.19
gMVP		0.41

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: rs748418783; hg19: chr19-13409523;