rs747238010
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 5P and 4B. PP2PP3_ModeratePP5_ModerateBS2
The NM_000702.4(ATP1A2):c.1811G>A(p.Arg604Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000682 in 1,614,030 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000055 ( 0 hom. )
Consequence
ATP1A2
NM_000702.4 missense
NM_000702.4 missense
Scores
10
6
3
Clinical Significance
Conservation
PhyloP100: 9.98
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 Uncertain_significance. Variant got 1 ACMG points.
PP2
?
Missense variant where missense usually causes diseases, ATP1A2
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.911
PP5
?
Variant 1-160130581-G-A is Pathogenic according to our data. Variant chr1-160130581-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 567317.Status of the report is criteria_provided_single_submitter, 1 stars.
BS2
?
High AC in GnomAdExome4 at 8 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATP1A2 | NM_000702.4 | c.1811G>A | p.Arg604Gln | missense_variant | 13/23 | ENST00000361216.8 | |
ATP1A2 | XM_047421286.1 | c.920G>A | p.Arg307Gln | missense_variant | 6/16 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATP1A2 | ENST00000361216.8 | c.1811G>A | p.Arg604Gln | missense_variant | 13/23 | 1 | NM_000702.4 | P1 | |
ATP1A2 | ENST00000392233.7 | c.1811G>A | p.Arg604Gln | missense_variant | 13/23 | 5 | |||
ATP1A2 | ENST00000447527.1 | c.944G>A | p.Arg315Gln | missense_variant | 6/16 | 2 | |||
ATP1A2 | ENST00000472488.5 | n.1914G>A | non_coding_transcript_exon_variant | 13/20 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152158Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 0.00000547 AC: 8AN: 1461872Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5AN XY: 727234
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GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152158Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74342
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ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Familial hemiplegic migraine Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Feb 06, 2023 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 604 of the ATP1A2 protein (p.Arg604Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of ATP1A2-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 567317). 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 not expected to disrupt ATP1A2 protein function. This variant disrupts the p.Arg604 amino acid residue in ATP1A2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20837964). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Uncertain
D;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Pathogenic
D
MutationAssessor
Benign
N;.
MutationTaster
Benign
D;D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D
Sift4G
Benign
T;T
Polyphen
D;D
Vest4
MutPred
Gain of ubiquitination at K602 (P = 0.0554);Gain of ubiquitination at K602 (P = 0.0554);
MVP
MPC
ClinPred
D
GERP RS
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gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at