rs28933398

Variant names:

• chr1-160135845-T-C
• rs28933398
• NM_000702.4:c.2291T>C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP2 PP3_Strong PP5

The NM_000702.4(ATP1A2):​c.2291T>C​(p.Leu764Pro) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. L764L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATP1A2 NM_000702.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 7.80

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 Pathogenic. Variant got 10 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 9 uncertain in NM_000702.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the ATP1A2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 63 curated pathogenic missense variants (we use a threshold of 10). The gene has 10 curated benign missense variants. Gene score misZ: 4.7713 (above the threshold of 3.09). Trascript score misZ: 6.824 (above the threshold of 3.09). GenCC associations: The gene is linked to 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: MetaRNN computational evidence supports a deleterious effect, 0.976
• PP5: Variant 1-160135845-T-C is Pathogenic according to our data. Variant chr1-160135845-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 12917.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-160135845-T-C is described in Lovd as [Pathogenic]. Variant chr1-160135845-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP1A2	NM_000702.4	c.2291T>C	p.Leu764Pro	missense_variant	Exon 17 of 23	ENST00000361216.8	NP_000693.1
ATP1A2	XM_047421286.1	c.1400T>C	p.Leu467Pro	missense_variant	Exon 10 of 16		XP_047277242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP1A2	ENST00000361216.8	c.2291T>C	p.Leu764Pro	missense_variant	Exon 17 of 23	1	NM_000702.4	ENSP00000354490.3
ATP1A2	ENST00000392233.7	c.2291T>C	p.Leu764Pro	missense_variant	Exon 17 of 23	5		ENSP00000376066.3
ATP1A2	ENST00000447527.1	c.1421T>C	p.Leu474Pro	missense_variant	Exon 10 of 16	2		ENSP00000411705.1
ATP1A2	ENST00000472488.5	n.2394T>C		non_coding_transcript_exon_variant	Exon 17 of 20	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Migraine, familial hemiplegic, 2 Pathogenic:1

Feb 01, 2003

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Familial hemiplegic migraine Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

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	28
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.82	D;.
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Pathogenic	0.39	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Uncertain	-0.094	T
MutationAssessor	Pathogenic	3.2	M;.
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-5.2	D;D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0030	D;D
Polyphen		1.0	D;.
Vest4		0.98
MutPred		0.86		Loss of stability (P = 0.0044);Loss of stability (P = 0.0044);
MVP		1.0
MPC		3.3
ClinPred		1.0	D
GERP RS		4.4
Varity_R		0.94
gMVP		0.99

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: rs28933398; hg19: chr1-160105635;