rs1555762900

Positions:

• chr19-13317223-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP2

The NM_001127222.2(CACNA1A):​c.1444A>G​(p.Met482Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,494 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.44

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 5 ACMG points.

• PM1: In a repeat II (size 244) in uniprot entity CAC1A_HUMAN there are 11 pathogenic changes around while only 0 benign (100%) in NM_001127222.2
• 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). The gene has 137 curated pathogenic missense variants (we use a threshold of 10). The gene has 132 curated benign missense variants. GenCC has associacion of the 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.1444A>G	p.Met482Val	missense_variant	11/47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.1444A>G	p.Met482Val	missense_variant	11/47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.1447A>G	p.Met483Val	missense_variant	11/48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.1450A>G	p.Met484Val	missense_variant	11/47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.1447A>G	p.Met483Val	missense_variant	11/47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.1447A>G	p.Met483Val	missense_variant	11/47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.1447A>G	p.Met483Val	missense_variant	11/46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.1306A>G	p.Met436Val	missense_variant	10/46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.1447A>G	p.Met483Val	missense_variant	11/47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.1447A>G	p.Met483Val	missense_variant	11/48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.1447A>G	p.Met483Val	missense_variant	11/48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.1450A>G	p.Met484Val	missense_variant	11/47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.1447A>G	p.Met483Val	missense_variant	11/47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.1447A>G	p.Met483Val	missense_variant	11/47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.1447A>G	p.Met483Val	missense_variant	11/46	5		ENSP00000489777.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461494 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727004

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Mar 26, 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 (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with CACNA1A-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces methionine with valine at codon 483 of the CACNA1A protein (p.Met483Val). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and valine. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 29, 2019

Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 30679323) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.069	.;.;T;.;.;.;.;.;.;T;.;.;.;T;.
Eigen	Uncertain	0.19
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.88	D;D;D;D;D;D;D;D;.;D;D;D;D;D;D
M_CAP	Benign	0.073	D
MetaRNN	Uncertain	0.44	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Benign	1.1	.;.;.;.;L;.;.;L;.;.;.;.;L;.;.
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-2.7	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.49
Sift	Benign	0.061	.;T;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.24	T;T;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.24
MutPred		0.39		Loss of helix (P = 0.0626);.;Loss of helix (P = 0.0626);Loss of helix (P = 0.0626);Loss of helix (P = 0.0626);.;Loss of helix (P = 0.0626);Loss of helix (P = 0.0626);Loss of helix (P = 0.0626);Loss of helix (P = 0.0626);Loss of helix (P = 0.0626);.;Loss of helix (P = 0.0626);.;Loss of helix (P = 0.0626);
MVP		0.82
MPC		1.3
ClinPred		0.82	D
GERP RS		5.8
Varity_R		0.30
gMVP		0.57

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: rs1555762900; hg19: chr19-13428037;