rs869025341
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP2PP3PP5
The NM_000702.4(ATP1A2):c.571G>A(p.Val191Met) variant causes a missense change. 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 Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. V191V) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
ATP1A2
NM_000702.4 missense
NM_000702.4 missense
Scores
3
11
5
Clinical Significance
Conservation
PhyloP100: 3.74
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 Likely_pathogenic. Variant got 7 ACMG points.
PM1
?
In a topological_domain Cytoplasmic (size 135) in uniprot entity AT1A2_HUMAN there are 12 pathogenic changes around while only 5 benign (71%) in NM_000702.4
PM2
?
Very rare variant in population databases, with high coverage;
PP2
?
Missense variant where missense usually causes diseases, ATP1A2
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.763
PP5
?
Variant 1-160124371-G-A is Pathogenic according to our data. Variant chr1-160124371-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 222078.Status of the report is no_assertion_criteria_provided, 0 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATP1A2 | NM_000702.4 | c.571G>A | p.Val191Met | missense_variant | 6/23 | ENST00000361216.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATP1A2 | ENST00000361216.8 | c.571G>A | p.Val191Met | missense_variant | 6/23 | 1 | NM_000702.4 | P1 | |
ATP1A2 | ENST00000392233.7 | c.571G>A | p.Val191Met | missense_variant | 6/23 | 5 | |||
ATP1A2 | ENST00000468587.1 | n.175G>A | non_coding_transcript_exon_variant | 2/3 | 2 | ||||
ATP1A2 | ENST00000472488.5 | n.674G>A | non_coding_transcript_exon_variant | 6/20 | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1460694Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 726494
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
AC:
0
AN:
1460694
Hom.:
Cov.:
32
AF XY:
AC XY:
0
AN XY:
726494
Gnomad4 AFR exome
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Migraine, familial hemiplegic, 2 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 10, 2021 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
Cadd
Pathogenic
Dann
Uncertain
DEOGEN2
Uncertain
D;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D
MetaSVM
Uncertain
D
MutationAssessor
Benign
L;.
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N
REVEL
Pathogenic
Sift
Benign
T;T
Sift4G
Benign
T;T
Polyphen
P;.
Vest4
MutPred
Gain of ubiquitination at K192 (P = 0.0577);Gain of ubiquitination at K192 (P = 0.0577);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at