rs750109401
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PP2PP3_ModerateBS2
The NM_000702.4(ATP1A2):c.1528C>T(p.Arg510Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,614,066 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R510H) has been classified as Uncertain significance.
Frequency
Consequence
NM_000702.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATP1A2 | NM_000702.4 | c.1528C>T | p.Arg510Cys | missense_variant | 12/23 | ENST00000361216.8 | |
ATP1A2 | XM_047421286.1 | c.637C>T | p.Arg213Cys | missense_variant | 5/16 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATP1A2 | ENST00000361216.8 | c.1528C>T | p.Arg510Cys | missense_variant | 12/23 | 1 | NM_000702.4 | P1 | |
ATP1A2 | ENST00000392233.7 | c.1528C>T | p.Arg510Cys | missense_variant | 12/23 | 5 | |||
ATP1A2 | ENST00000447527.1 | c.661C>T | p.Arg221Cys | missense_variant | 5/16 | 2 | |||
ATP1A2 | ENST00000472488.5 | n.1631C>T | non_coding_transcript_exon_variant | 12/20 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152176Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251366Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135890
GnomAD4 exome AF: 0.0000137 AC: 20AN: 1461890Hom.: 0 Cov.: 32 AF XY: 0.00000963 AC XY: 7AN XY: 727246
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152176Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74338
ClinVar
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 26, 2022 | The c.1528C>T (p.R510C) alteration is located in exon 12 (coding exon 12) of the ATP1A2 gene. This alteration results from a C to T substitution at nucleotide position 1528, causing the arginine (R) at amino acid position 510 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Familial hemiplegic migraine Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 21, 2023 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 510 of the ATP1A2 protein (p.Arg510Cys). This variant is present in population databases (rs750109401, gnomAD 0.002%). 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: 572079). 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 expected to disrupt ATP1A2 protein function with a positive predictive value of 80%. 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at