1-160127639-G-A
Variant summary
Our verdict is Likely benign. The variant received -6 ACMG points: 3P and 9B. PM1PP2BP4_StrongBP6BS1
The NM_000702.4(ATP1A2):c.836G>A(p.Arg279Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000133 in 1,614,236 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict 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. R279W) has been classified as Uncertain significance.
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.836G>A | p.Arg279Gln | missense_variant | Exon 8 of 23 | ENST00000361216.8 | NP_000693.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ATP1A2 | ENST00000361216.8 | c.836G>A | p.Arg279Gln | missense_variant | Exon 8 of 23 | 1 | NM_000702.4 | ENSP00000354490.3 | ||
ATP1A2 | ENST00000392233.7 | c.836G>A | p.Arg279Gln | missense_variant | Exon 8 of 23 | 5 | ENSP00000376066.3 | |||
ATP1A2 | ENST00000472488.5 | n.939G>A | non_coding_transcript_exon_variant | Exon 8 of 20 | 2 | |||||
ATP1A2 | ENST00000447527.1 | c.-35G>A | upstream_gene_variant | 2 | ENSP00000411705.1 |
Frequencies
GnomAD3 genomes AF: 0.000486 AC: 74AN: 152236Hom.: 1 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.000115 AC: 29AN: 251426 AF XY: 0.0000662 show subpopulations
GnomAD4 exome AF: 0.0000958 AC: 140AN: 1461882Hom.: 0 Cov.: 33 AF XY: 0.0000798 AC XY: 58AN XY: 727240 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.000486 AC: 74AN: 152354Hom.: 1 Cov.: 32 AF XY: 0.000416 AC XY: 31AN XY: 74508 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
not provided Uncertain:1
- -
not specified Benign:1
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
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. -
ATP1A2-related disorder Benign:1
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Familial hemiplegic migraine Benign:1
- -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at