rs142348542
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 1P and 10B. PP2BP4_ModerateBS1BS2
The NM_000702.4(ATP1A2):c.1474G>A(p.Glu492Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000688 in 1,614,204 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000702.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
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ATP1A2 | NM_000702.4 | c.1474G>A | p.Glu492Lys | missense_variant | Exon 12 of 23 | ENST00000361216.8 | NP_000693.1 | |
ATP1A2 | XM_047421286.1 | c.583G>A | p.Glu195Lys | missense_variant | Exon 5 of 16 | XP_047277242.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ATP1A2 | ENST00000361216.8 | c.1474G>A | p.Glu492Lys | missense_variant | Exon 12 of 23 | 1 | NM_000702.4 | ENSP00000354490.3 | ||
ATP1A2 | ENST00000392233.7 | c.1474G>A | p.Glu492Lys | missense_variant | Exon 12 of 23 | 5 | ENSP00000376066.3 | |||
ATP1A2 | ENST00000447527.1 | c.604G>A | p.Glu202Lys | missense_variant | Exon 5 of 16 | 2 | ENSP00000411705.1 | |||
ATP1A2 | ENST00000472488.5 | n.1577G>A | non_coding_transcript_exon_variant | Exon 12 of 20 | 2 |
Frequencies
GnomAD3 genomes AF: 0.000506 AC: 77AN: 152210Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000442 AC: 111AN: 251174Hom.: 0 AF XY: 0.000479 AC XY: 65AN XY: 135838
GnomAD4 exome AF: 0.000707 AC: 1033AN: 1461876Hom.: 2 Cov.: 32 AF XY: 0.000700 AC XY: 509AN XY: 727234
GnomAD4 genome AF: 0.000505 AC: 77AN: 152328Hom.: 0 Cov.: 32 AF XY: 0.000443 AC XY: 33AN XY: 74482
ClinVar
Submissions by phenotype
not provided Uncertain:6
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Published in vitro functional studies suggest this variant results in partial loss of function due to reduced cell survival when transfected into HeLa cells (PMID: 18056581); Reported previously in a five-year-old male with hemiplegic migraine and his mother who had a history of migraines with aura but no hemiplegic attacks (PMID: 18056581); Reported in both affected individuals and healthy controls in a case-control study of patients with migraines (PMID: 36044383); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 18957371, 34426522, 35982159, 18184292, 37234784, 33057194, 36044383, 18056581) -
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Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is higher than would generally be expected for pathogenic variants in this gene (http://gnomad.broadinstitute.org). This variant is statistically more frequent in migraine-affected individuals than in the general population and/or healthy controls, suggesting in may be a risk factor for migraines. This variant has been identified in at least one individual with familial hemiplegic migraine. Assessment of experimental evidence suggests this variant results in abnormal protein function, although it shows a milder decrease in function than other known pathogenic variants. (PMID:18056581) -
ATP1A2-related disorder Uncertain:1
The ATP1A2 c.1474G>A variant is predicted to result in the amino acid substitution p.Glu492Lys. This variant was reported in an individual with hemiplegic migraines and also in his mother who presented with migraines lacking hemiplegia. In vitro studies indicated that this variant may partially impact protein function (de Vries et al. 2007. PubMed ID: 18056581). However, this variant is reported on 0.081% of alleles in individuals of European (Non-Finnish) descent in gnomAD, which is significantly more common than any established pathogenic variant in this gene. Additionally, this variant was not statistically more prevalent in affected individuals compared to presumably asymptomatic controls (Markel et al. 2022. PubMed ID: 36044383). Although we suspect c.1474G>A (p.Glu492Lys) may be benign, the clinical significance of this variant is currently classified as uncertain due to the absence of conclusive functional and genetic evidence. -
not specified Benign:1
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Inborn genetic diseases Benign:1
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Migraine, familial hemiplegic, 2 Benign:1
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Familial hemiplegic migraine Benign:1
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Alternating hemiplegia of childhood 1 Benign:1
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at