rs121918612

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Moderate

The ENST00000361216.8(ATP1A2):​c.901G>A​(p.Gly301Arg) 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. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G301E) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Consequence

ATP1A2
ENST00000361216.8 missense

Scores

17
1
1

Clinical Significance

Pathogenic criteria provided, single submitter P:2O:1

Conservation

PhyloP100: 9.97
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 13 ACMG points.

PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in ENST00000361216.8
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr1-160127705-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2020422.Status of the report is criteria_provided_single_submitter, 1 stars.
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
MetaRNN computational evidence supports a deleterious effect, 0.992
PP5
Variant 1-160127704-G-A is Pathogenic according to our data. Variant chr1-160127704-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 12922.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-160127704-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ATP1A2NM_000702.4 linkuse as main transcriptc.901G>A p.Gly301Arg missense_variant 8/23 ENST00000361216.8 NP_000693.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ATP1A2ENST00000361216.8 linkuse as main transcriptc.901G>A p.Gly301Arg missense_variant 8/231 NM_000702.4 ENSP00000354490 P1
ATP1A2ENST00000392233.7 linkuse as main transcriptc.901G>A p.Gly301Arg missense_variant 8/235 ENSP00000376066
ATP1A2ENST00000447527.1 linkuse as main transcriptc.34G>A p.Gly12Arg missense_variant 1/162 ENSP00000411705
ATP1A2ENST00000472488.5 linkuse as main transcriptn.1004G>A non_coding_transcript_exon_variant 8/202

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
33
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:2Other:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Familial hemiplegic migraine Pathogenic:1Other:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpOct 24, 2022For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects ATP1A2 function (PMID: 19372756, 21398422). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ATP1A2 protein function. ClinVar contains an entry for this variant (Variation ID: 12922). This missense change has been observed in individuals with familial hemiplegic migraine (PMID: 15459825, 21398422). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 301 of the ATP1A2 protein (p.Gly301Arg). -
not provided, no classification providedliterature onlyGeneReviews-Severe phenotype reported -
Migraine, familial hemiplegic, 2 Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMSep 01, 2004- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.50
D
BayesDel_noAF
Pathogenic
0.48
CADD
Pathogenic
33
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.96
D;.
Eigen
Pathogenic
0.74
Eigen_PC
Pathogenic
0.71
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.99
D;D
M_CAP
Pathogenic
0.66
D
MetaRNN
Pathogenic
0.99
D;D
MetaSVM
Uncertain
0.66
D
MutationAssessor
Pathogenic
3.8
H;.
MutationTaster
Benign
1.0
A;A
PrimateAI
Pathogenic
0.92
D
PROVEAN
Pathogenic
-6.7
D;D
REVEL
Pathogenic
0.94
Sift
Pathogenic
0.0
D;D
Sift4G
Pathogenic
0.0
D;D
Polyphen
1.0
D;.
Vest4
0.95
MutPred
0.98
Gain of methylation at G301 (P = 0.0062);Gain of methylation at G301 (P = 0.0062);
MVP
0.98
MPC
2.0
ClinPred
1.0
D
GERP RS
4.9
Varity_R
0.98
gMVP
1.0

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs121918612; hg19: chr1-160097494; API