rs139229302
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Variant summary
Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2
The NM_000702.4(ATP1A2):āc.627T>Cā(p.Cys209Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000197 in 1,606,640 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).
Frequency
Genomes: š 0.000046 ( 0 hom., cov: 32)
Exomes š: 0.00021 ( 0 hom. )
Consequence
ATP1A2
NM_000702.4 synonymous
NM_000702.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.328
Genes affected
ATP1A2 (HGNC:800): (ATPase Na+/K+ transporting subunit alpha 2) The protein encoded by this gene belongs to the family of P-type cation transport ATPases, and to the subfamily of Na+/K+ -ATPases. Na+/K+ -ATPase is an integral membrane protein responsible for establishing and maintaining the electrochemical gradients of Na and K ions across the plasma membrane. These gradients are essential for osmoregulation, for sodium-coupled transport of a variety of organic and inorganic molecules, and for electrical excitability of nerve and muscle. This enzyme is composed of two subunits, a large catalytic subunit (alpha) and a smaller glycoprotein subunit (beta). The catalytic subunit of Na+/K+ -ATPase is encoded by multiple genes. This gene encodes an alpha 2 subunit. Mutations in this gene result in familial basilar or hemiplegic migraines, and in a rare syndrome known as alternating hemiplegia of childhood. [provided by RefSeq, Oct 2008]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -14 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.63).
BP6
Variant 1-160124427-T-C is Benign according to our data. Variant chr1-160124427-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 293129.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=1}.
BP7
Synonymous conserved (PhyloP=0.328 with no splicing effect.
BS1
Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.000212 (309/1454570) while in subpopulation NFE AF= 0.000277 (307/1108756). AF 95% confidence interval is 0.000251. There are 0 homozygotes in gnomad4_exome. There are 152 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High AC in GnomAd4 at 7 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ATP1A2 | NM_000702.4 | c.627T>C | p.Cys209Cys | synonymous_variant | 6/23 | ENST00000361216.8 | NP_000693.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ATP1A2 | ENST00000361216.8 | c.627T>C | p.Cys209Cys | synonymous_variant | 6/23 | 1 | NM_000702.4 | ENSP00000354490.3 | ||
ATP1A2 | ENST00000392233.7 | c.627T>C | p.Cys209Cys | synonymous_variant | 6/23 | 5 | ENSP00000376066.3 | |||
ATP1A2 | ENST00000468587.1 | n.231T>C | non_coding_transcript_exon_variant | 2/3 | 2 | |||||
ATP1A2 | ENST00000472488.5 | n.730T>C | non_coding_transcript_exon_variant | 6/20 | 2 |
Frequencies
GnomAD3 genomes AF: 0.0000460 AC: 7AN: 152070Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000757 AC: 18AN: 237718Hom.: 0 AF XY: 0.0000625 AC XY: 8AN XY: 128048
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GnomAD4 exome AF: 0.000212 AC: 309AN: 1454570Hom.: 0 Cov.: 32 AF XY: 0.000210 AC XY: 152AN XY: 722738
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GnomAD4 genome AF: 0.0000460 AC: 7AN: 152070Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74264
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:4
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Migraine, familial hemiplegic, 2 Uncertain:1
Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 16, 2020 | 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. - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Dec 31, 2019 | - - |
Familial hemiplegic migraine Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 19, 2024 | - - |
Alternating hemiplegia of childhood 1 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. - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at