chr1-160135992-T-A
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Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PP2PP3_StrongPP5_Very_Strong
The NM_000702.4(ATP1A2):c.2438T>A(p.Met813Lys) 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. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Consequence
ATP1A2
NM_000702.4 missense, splice_region
NM_000702.4 missense, splice_region
Scores
13
5
1
Splicing: ADA: 0.7317
2
Clinical Significance
Conservation
PhyloP100: 8.00
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 17 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, 5 uncertain 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, 0.942
PP5
Variant 1-160135992-T-A is Pathogenic according to our data. Variant chr1-160135992-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 204898.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATP1A2 | NM_000702.4 | c.2438T>A | p.Met813Lys | missense_variant, splice_region_variant | 17/23 | ENST00000361216.8 | |
ATP1A2 | XM_047421286.1 | c.1547T>A | p.Met516Lys | missense_variant, splice_region_variant | 10/16 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATP1A2 | ENST00000361216.8 | c.2438T>A | p.Met813Lys | missense_variant, splice_region_variant | 17/23 | 1 | NM_000702.4 | P1 | |
ATP1A2 | ENST00000392233.7 | c.2438T>A | p.Met813Lys | missense_variant, splice_region_variant | 17/23 | 5 | |||
ATP1A2 | ENST00000447527.1 | c.1571T>A | p.Met524Lys | missense_variant, splice_region_variant | 10/16 | 2 | |||
ATP1A2 | ENST00000472488.5 | n.2541T>A | splice_region_variant, non_coding_transcript_exon_variant | 17/20 | 2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 33
GnomAD4 exome
Cov.:
33
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:2Uncertain:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Developmental and epileptic encephalopathy 98 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | - | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 09, 2016 | p.Met813Lys (ATG>AAG): c.2438 T>A in exon 17 of the ATP1A2 gene (NM_000702.3). The Met813Lys missense change has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The amino acid substitution is non-conservative as a uncharged, non-polar Methionine residue is replaced by a positively charged, polar Lysine residue. Met813Lys alters a conserved position in the M6 transmembrane domain of the ATP1A2 protein and several in-silico algorithms predict it may be damaging to the structure/function of the protein. The Met813Lys variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded. - |
Migraine, familial hemiplegic, 2 Uncertain:1
Uncertain significance, flagged submission | clinical testing | Baylor Genetics | Sep 01, 2017 | Likely pathogenicity based on finding it de novo in a 2-year-old male with developmental delay, seizure disorder, alternating hemiplegic migraine, and left hemiparesis. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D;.
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
H;.
MutationTaster
Benign
D;D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D
Sift4G
Pathogenic
D;D
Polyphen
P;.
Vest4
MutPred
Gain of ubiquitination at M813 (P = 0.0203);Gain of ubiquitination at M813 (P = 0.0203);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at