rs1461860929

Positions:

• chr1-160135839-G-C
• chr1-160135839-G-T

Variant summary

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

The NM_000702.4(ATP1A2):​c.2285G>C​(p.Gly762Ala) variant causes a missense, splice region 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. 13/23 in silico tools predict a damaging outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATP1A2 NM_000702.4 missense, splice_region
• Scores: Splicing: ADA: 0.9996
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.35

Genes affected

ATP1A2 (HGNC:800): (ATPase Na+/K+ transporting subunit alpha 2) The protein encoded by this gene belongs to the family of P-type cation transport ATPases, and to the subfamily of Na+/K+ -ATPases. Na+/K+ -ATPase is an integral membrane protein responsible for establishing and maintaining the electrochemical gradients of Na and K ions across the plasma membrane. These gradients are essential for osmoregulation, for sodium-coupled transport of a variety of organic and inorganic molecules, and for electrical excitability of nerve and muscle. This enzyme is composed of two subunits, a large catalytic subunit (alpha) and a smaller glycoprotein subunit (beta). The catalytic subunit of Na+/K+ -ATPase is encoded by multiple genes. This gene encodes an alpha 2 subunit. Mutations in this gene result in familial basilar or hemiplegic migraines, and in a rare syndrome known as alternating hemiplegia of childhood. [provided by RefSeq, Oct 2008]

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 gene, where missense usually causes diseases (based on misZ statistic), ATP1A2. . Gene score misZ 4.7713 (greater than the threshold 3.09). Trascript score misZ 6.824 (greater than threshold 3.09). GenCC has associacion of gene with fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies, alternating hemiplegia of childhood, hemiplegic migraine-developmental and epileptic encephalopathy spectrum, familial or sporadic hemiplegic migraine, alternating hemiplegia of childhood 1, developmental and epileptic encephalopathy 98, migraine, familial hemiplegic, 2.
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP1A2	NM_000702.4	c.2285G>C	p.Gly762Ala	missense_variant, splice_region_variant	17/23	ENST00000361216.8	NP_000693.1
ATP1A2	XM_047421286.1	c.1394G>C	p.Gly465Ala	missense_variant, splice_region_variant	10/16		XP_047277242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP1A2	ENST00000361216.8	c.2285G>C	p.Gly762Ala	missense_variant, splice_region_variant	17/23	1	NM_000702.4	ENSP00000354490	P1
ATP1A2	ENST00000392233.7	c.2285G>C	p.Gly762Ala	missense_variant, splice_region_variant	17/23	5		ENSP00000376066
ATP1A2	ENST00000447527.1	c.1418G>C	p.Gly473Ala	missense_variant, splice_region_variant	10/16	2		ENSP00000411705
ATP1A2	ENST00000472488.5	n.2388G>C		splice_region_variant, non_coding_transcript_exon_variant	17/20	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial hemiplegic migraine Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 29, 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 sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. 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 and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with ATP1A2-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with alanine at codon 762 of the ATP1A2 protein (p.Gly762Ala). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and alanine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D;.
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.4	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-4.4	D;D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.94
MutPred		0.91		Loss of stability (P = 0.1717);Loss of stability (P = 0.1717);
MVP		0.97
MPC		2.6
ClinPred		1.0	D
GERP RS		4.4
Varity_R		0.82
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.98
SpliceAI score (max)		0.070		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: rs1461860929; hg19: chr1-160105629;