1-160135449-G-A
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Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP2PP3
The NM_000702.4(ATP1A2):c.2131G>A(p.Val711Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,894 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 Uncertain significance (★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000027 ( 0 hom. )
Consequence
ATP1A2
NM_000702.4 missense
NM_000702.4 missense
Scores
9
7
3
Clinical Significance
Conservation
PhyloP100: 9.97
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 6 ACMG points.
PM1
In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_000702.4
PM2
Very rare variant in population databases, with high coverage;
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, 0.801
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATP1A2 | NM_000702.4 | c.2131G>A | p.Val711Met | missense_variant | 16/23 | ENST00000361216.8 | |
ATP1A2 | XM_047421286.1 | c.1240G>A | p.Val414Met | missense_variant | 9/16 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATP1A2 | ENST00000361216.8 | c.2131G>A | p.Val711Met | missense_variant | 16/23 | 1 | NM_000702.4 | P1 | |
ATP1A2 | ENST00000392233.7 | c.2131G>A | p.Val711Met | missense_variant | 16/23 | 5 | |||
ATP1A2 | ENST00000447527.1 | c.1264G>A | p.Val422Met | missense_variant | 9/16 | 2 | |||
ATP1A2 | ENST00000472488.5 | n.2234G>A | non_coding_transcript_exon_variant | 16/20 | 2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
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32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251438Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135886
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GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461894Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1AN XY: 727248
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GnomAD4 genome Cov.: 32
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 27, 2019 | The p.V711M variant (also known as c.2131G>A), located in coding exon 16 of the ATP1A2 gene, results from a G to A substitution at nucleotide position 2131. The valine at codon 711 is replaced by methionine, an amino acid with highly similar properties. This variant was previously reported in one individual with early-onset sporadic hemiplegic migraine and found to be inherited from a parent with migraines without aura (Riant F et al. Neurology., 2010 Sep;75(11):967-72). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear. - |
Familial hemiplegic migraine Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Apr 20, 2017 | In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with an ATP1A2-related disease. This sequence change replaces valine with methionine at codon 711 of the ATP1A2 protein (p.Val711Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
D;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D
MetaSVM
Uncertain
D
MutationAssessor
Benign
L;.
MutationTaster
Benign
D;D
PrimateAI
Pathogenic
D
PROVEAN
Benign
N;N
REVEL
Pathogenic
Sift
Pathogenic
D;D
Sift4G
Uncertain
T;T
Polyphen
D;.
Vest4
MutPred
Gain of disorder (P = 0.1402);Gain of disorder (P = 0.1402);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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Calibrated prediction
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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