chr1-160121226-G-A
Variant summary
Our verdict is Likely benign. The variant received -6 ACMG points: 1P and 7B. PP2BP4_ModerateBP6BS1
The NM_000702.4(ATP1A2):c.152G>A(p.Arg51His) variant causes a missense change. The variant allele was found at a frequency of 0.000259 in 1,614,222 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R51C) has been classified as Likely benign.
Frequency
Consequence
NM_000702.4 missense
Scores
Clinical Significance
Conservation
Publications
- hemiplegic migraine-developmental and epileptic encephalopathy spectrumInheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
- migraine, familial hemiplegic, 2Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
- alternating hemiplegia of childhood 1Inheritance: AD Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
- developmental and epileptic encephalopathy 98Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
- fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic faciesInheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
- alternating hemiplegia of childhoodInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- familial or sporadic hemiplegic migraineInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Likely_benign. The variant received -6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ATP1A2 | NM_000702.4 | c.152G>A | p.Arg51His | missense_variant | Exon 3 of 23 | ENST00000361216.8 | NP_000693.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ATP1A2 | ENST00000361216.8 | c.152G>A | p.Arg51His | missense_variant | Exon 3 of 23 | 1 | NM_000702.4 | ENSP00000354490.3 | ||
ATP1A2 | ENST00000392233.7 | c.152G>A | p.Arg51His | missense_variant | Exon 3 of 23 | 5 | ENSP00000376066.3 | |||
ATP1A2 | ENST00000472488.5 | n.255G>A | non_coding_transcript_exon_variant | Exon 3 of 20 | 2 | |||||
ATP1A2 | ENST00000478587.1 | n.432G>A | non_coding_transcript_exon_variant | Exon 2 of 2 | 3 |
Frequencies
GnomAD3 genomes AF: 0.000112 AC: 17AN: 152236Hom.: 0 Cov.: 33 show subpopulations
GnomAD2 exomes AF: 0.000123 AC: 31AN: 251478 AF XY: 0.000125 show subpopulations
GnomAD4 exome AF: 0.000274 AC: 401AN: 1461868Hom.: 0 Cov.: 32 AF XY: 0.000265 AC XY: 193AN XY: 727232 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.000112 AC: 17AN: 152354Hom.: 0 Cov.: 33 AF XY: 0.000121 AC XY: 9AN XY: 74508 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
not specified Uncertain:2
A variant of uncertain significance has been identified in the ATP1A2 gene. The R51H variant has been reported in association with migraine without aura; however, functional studies showed no significant differences between this variant and the wild type protein (Swarts et al., 2013). The R51H variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R51H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -
Variant summary: ATP1A2 c.152G>A (p.Arg51His) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 251478 control chromosomes (gnomAD). c.152G>A has been reported in the literature in a family with migraine without aura (Swarts_2013). This report does not provide unequivocal conclusions about association of the variant with Familial Hemiplegic Migraine. At least one publication reports experimental evidence evaluating an impact on protein function (Swarts_2013). These results showed no damaging effect of this variant. The following publication has been ascertained in the context of this evaluation (PMID: 23954377). ClinVar contains an entry for this variant (Variation ID: 372793). Based on the evidence outlined above, the variant was classified as uncertain significance. -
ATP1A2-related disorder Uncertain:1
The ATP1A2 c.152G>A variant is predicted to result in the amino acid substitution p.Arg51His. This variant has been reported in a three-generation Portuguese family with migraine without aura, however functional analysis of this variant showed results similar to wildtype (Swarts et al. 2013. PubMed ID: 23954377). This variant is reported in 0.020% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Familial hemiplegic migraine Uncertain:1
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 51 of the ATP1A2 protein (p.Arg51His). This variant is present in population databases (rs144106169, gnomAD 0.02%). This missense change has been observed in individual(s) with migraine without aura (PMID: 23954377). ClinVar contains an entry for this variant (Variation ID: 372793). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt ATP1A2 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change does not substantially affect ATP1A2 function (PMID: 23954377). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at