rs1555774867

Positions:

• chr19-13365458-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP2 PP3

The NM_001127222.2(CACNA1A):​c.643G>A​(p.Val215Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,370 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 31)
  • 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: 7.81

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a repeat I (size 278) in uniprot entity CAC1A_HUMAN there are 11 pathogenic changes around while only 1 benign (92%) 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). 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.768

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.643G>A	p.Val215Ile	missense_variant	5/47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.643G>A	p.Val215Ile	missense_variant	5/47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.643G>A	p.Val215Ile	missense_variant	5/48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.643G>A	p.Val215Ile	missense_variant	5/47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.643G>A	p.Val215Ile	missense_variant	5/47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.643G>A	p.Val215Ile	missense_variant	5/47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.643G>A	p.Val215Ile	missense_variant	5/46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.502G>A	p.Val168Ile	missense_variant	4/46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.643G>A	p.Val215Ile	missense_variant	5/47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.643G>A	p.Val215Ile	missense_variant	5/48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.643G>A	p.Val215Ile	missense_variant	5/48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.643G>A	p.Val215Ile	missense_variant	5/47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.643G>A	p.Val215Ile	missense_variant	5/47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.643G>A	p.Val215Ile	missense_variant	5/47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.643G>A	p.Val215Ile	missense_variant	5/46	5		ENSP00000489777.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461370 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726968

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Athena Diagnostics

Feb 21, 2017

- -

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

May 08, 2017

In summary, this variant is a novel missense change with uncertain impact on protein function. 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 disruptive, but these predictions have not been confirmed by published functional studies. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a CACNA1A-related disease. This sequence change replaces valine with isoleucine at codon 215 of the CACNA1A protein (p.Val215Ile). The valine residue is highly conserved and there is a small physicochemical difference between valine and isoleucine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.70	.;D;T;.;.;.;.;.;.;T;.;.;.;T;.
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D;.;D;D;D;D;D;D
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.77	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Uncertain	2.4	.;M;.;.;M;.;.;M;.;.;.;.;M;.;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.84	.;N;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0070	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Uncertain	0.014	D;D;.;.;.;.;.;.;.;.;.;D;.;.;.
Polyphen		0.95	.;P;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.37
MutPred		0.60		Gain of MoRF binding (P = 0.2078);Gain of MoRF binding (P = 0.2078);Gain of MoRF binding (P = 0.2078);Gain of MoRF binding (P = 0.2078);Gain of MoRF binding (P = 0.2078);.;Gain of MoRF binding (P = 0.2078);Gain of MoRF binding (P = 0.2078);Gain of MoRF binding (P = 0.2078);Gain of MoRF binding (P = 0.2078);Gain of MoRF binding (P = 0.2078);Gain of MoRF binding (P = 0.2078);Gain of MoRF binding (P = 0.2078);Gain of MoRF binding (P = 0.2078);Gain of MoRF binding (P = 0.2078);
MVP		0.89
MPC		1.6
ClinPred		0.96	D
GERP RS		4.5
Varity_R		0.54
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1555774867; hg19: chr19-13476272;