chr1-160130222-G-A
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2BP6BS1BS2
The ENST00000361216.8(ATP1A2):c.1582G>A(p.Asp528Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000109 in 1,614,068 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. D528G) has been classified as Uncertain significance.
Frequency
Consequence
ENST00000361216.8 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ATP1A2 | NM_000702.4 | c.1582G>A | p.Asp528Asn | missense_variant | 12/23 | ENST00000361216.8 | NP_000693.1 | |
ATP1A2 | XM_047421286.1 | c.691G>A | p.Asp231Asn | missense_variant | 5/16 | XP_047277242.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ATP1A2 | ENST00000361216.8 | c.1582G>A | p.Asp528Asn | missense_variant | 12/23 | 1 | NM_000702.4 | ENSP00000354490 | P1 | |
ATP1A2 | ENST00000392233.7 | c.1582G>A | p.Asp528Asn | missense_variant | 12/23 | 5 | ENSP00000376066 | |||
ATP1A2 | ENST00000447527.1 | c.715G>A | p.Asp239Asn | missense_variant | 5/16 | 2 | ENSP00000411705 | |||
ATP1A2 | ENST00000472488.5 | n.1685G>A | non_coding_transcript_exon_variant | 12/20 | 2 |
Frequencies
GnomAD3 genomes AF: 0.0000854 AC: 13AN: 152180Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000676 AC: 17AN: 251440Hom.: 0 AF XY: 0.0000662 AC XY: 9AN XY: 135908
GnomAD4 exome AF: 0.000111 AC: 163AN: 1461888Hom.: 0 Cov.: 32 AF XY: 0.0000990 AC XY: 72AN XY: 727244
GnomAD4 genome AF: 0.0000854 AC: 13AN: 152180Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5AN XY: 74332
ClinVar
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jan 09, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | May 01, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 14, 2024 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Located within the Phosphorylation Subdomain (PMID: 18184292); This variant is associated with the following publications: (PMID: 18184292) - |
Familial hemiplegic migraine Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 15, 2023 | This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 528 of the ATP1A2 protein (p.Asp528Asn). This variant is present in population databases (rs374501280, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with ATP1A2-related conditions. ClinVar contains an entry for this variant (Variation ID: 432411). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ATP1A2 protein function. 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. - |
Migraine, familial hemiplegic, 2 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. - |
Alternating hemiplegia of childhood 1 Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at