19-13317297-A-T

Variant names:

• chr19-13317297-A-T
• rs768383869
• NM_001127222.2:c.1370T>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_001127222.2(CACNA1A):​c.1370T>A​(p.Ile457Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.31

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 4 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.801

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.1370T>A	p.Ile457Asn	missense_variant	Exon 11 of 47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.1370T>A	p.Ile457Asn	missense_variant	Exon 11 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.1373T>A	p.Ile458Asn	missense_variant	Exon 11 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.1376T>A	p.Ile459Asn	missense_variant	Exon 11 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.1373T>A	p.Ile458Asn	missense_variant	Exon 11 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.1373T>A	p.Ile458Asn	missense_variant	Exon 11 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.1373T>A	p.Ile458Asn	missense_variant	Exon 11 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.1232T>A	p.Ile411Asn	missense_variant	Exon 10 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.1373T>A	p.Ile458Asn	missense_variant	Exon 11 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.1373T>A	p.Ile458Asn	missense_variant	Exon 11 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.1373T>A	p.Ile458Asn	missense_variant	Exon 11 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.1376T>A	p.Ile459Asn	missense_variant	Exon 11 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.1373T>A	p.Ile458Asn	missense_variant	Exon 11 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.1373T>A	p.Ile458Asn	missense_variant	Exon 11 of 47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.1373T>A	p.Ile458Asn	missense_variant	Exon 11 of 46	5		ENSP00000489777.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Feb 27, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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. This variant has not been reported in the literature in individuals with CACNA1A-related disease. This sequence change replaces isoleucine with asparagine at codon 458 of the CACNA1A protein (p.Ile458Asn). The isoleucine residue is moderately conserved and there is a large physicochemical difference between isoleucine and asparagine. This variant is not present in population databases (ExAC no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.079	.;.;T;.;.;.;.;.;.;T;.;.;.;T;.
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.88	D;D;D;D;D;D;D;D;.;D;D;D;D;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.80	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.093	D
MutationAssessor	Benign	1.8	.;.;.;.;L;.;.;L;.;.;.;.;L;.;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-5.7	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.61
Sift	Uncertain	0.014	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Uncertain	0.043	D;D;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.69
MutPred		0.53		Gain of loop (P = 0.0166);.;Gain of loop (P = 0.0166);Gain of loop (P = 0.0166);Gain of loop (P = 0.0166);.;Gain of loop (P = 0.0166);Gain of loop (P = 0.0166);Gain of loop (P = 0.0166);Gain of loop (P = 0.0166);Gain of loop (P = 0.0166);.;Gain of loop (P = 0.0166);.;Gain of loop (P = 0.0166);
MVP		0.85
MPC		2.8
ClinPred		0.98	D
GERP RS		5.8
Varity_R		0.71
gMVP		0.81

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: rs768383869; hg19: chr19-13428111;