rs1063125

Positions:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000702.4(ATP1A2):c.1119G>A(p.Ser373=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.194 in 1,613,918 control chromosomes in the GnomAD database, including 31,710 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.19 ( 2807 hom., cov: 31)

Exomes 𝑓: 0.19 ( 28903 hom. )

Consequence

ATP1A2
NM_000702.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: -6.55

Variant links:

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]

ATP1A2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BP6

Variant 1-160128753-G-A is Benign according to our data. Variant chr1-160128753-G-A is described in ClinVar as [Benign]. Clinvar id is 128477.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-160128753-G-A is described in Lovd as [Benign]. Variant chr1-160128753-G-A is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-6.55 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.314 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP1A2	NM_000702.4 linkuse as main transcript	c.1119G>A	p.Ser373=	synonymous_variant	9/23	ENST00000361216.8	NP_000693.1
ATP1A2	XM_047421286.1 linkuse as main transcript	c.228G>A	p.Ser76=	synonymous_variant	2/16		XP_047277242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
ATP1A2	ENST00000361216.8 linkuse as main transcript	c.1119G>A	p.Ser373=	synonymous_variant	9/23	1	NM_000702.4	ENSP00000354490	P1
ATP1A2	ENST00000392233.7 linkuse as main transcript	c.1119G>A	p.Ser373=	synonymous_variant	9/23	5		ENSP00000376066
ATP1A2	ENST00000447527.1 linkuse as main transcript	c.252G>A	p.Ser84=	synonymous_variant	2/16	2		ENSP00000411705
ATP1A2	ENST00000472488.5 linkuse as main transcript	n.1222G>A		non_coding_transcript_exon_variant	9/20	2

Frequencies

GnomAD3 genomes

AF:

0.188

AC:

28522

AN:

151908

Hom.:

2798

Cov.:

show subpopulations

Gnomad AFR

AF:

0.192

Gnomad AMI

AF:

0.237

Gnomad AMR

AF:

0.141

Gnomad ASJ

AF:

0.181

Gnomad EAS

AF:

0.159

Gnomad SAS

AF:

0.328

Gnomad FIN

AF:

0.139

Gnomad MID

AF:

0.196

Gnomad NFE

AF:

0.195

Gnomad OTH

AF:

0.200

GnomAD3 exomes

AF:

0.190

AC:

47782

AN:

251460

Hom.:

5136

AF XY:

0.199

AC XY:

27101

AN XY:

135908

show subpopulations

Gnomad AFR exome

AF:

0.186

Gnomad AMR exome

AF:

0.0890

Gnomad ASJ exome

AF:

0.178

Gnomad EAS exome

AF:

0.160

Gnomad SAS exome

AF:

0.324

Gnomad FIN exome

AF:

0.141

Gnomad NFE exome

AF:

0.200

Gnomad OTH exome

AF:

0.197

GnomAD4 exome

AF:

0.195

AC:

284353

AN:

1461892

Hom.:

28903

Cov.:

AF XY:

0.199

AC XY:

144823

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.188

Gnomad4 AMR exome

AF:

0.0934

Gnomad4 ASJ exome

AF:

0.178

Gnomad4 EAS exome

AF:

0.195

Gnomad4 SAS exome

AF:

0.317

Gnomad4 FIN exome

AF:

0.141

Gnomad4 NFE exome

AF:

0.192

Gnomad4 OTH exome

AF:

0.194

GnomAD4 genome

AF:

0.188

AC:

28552

AN:

152026

Hom.:

2807

Cov.:

AF XY:

0.187

AC XY:

13905

AN XY:

74318

show subpopulations

Gnomad4 AFR

AF:

0.192

Gnomad4 AMR

AF:

0.141

Gnomad4 ASJ

AF:

0.181

Gnomad4 EAS

AF:

0.160

Gnomad4 SAS

AF:

0.327

Gnomad4 FIN

AF:

0.139

Gnomad4 NFE

AF:

0.195

Gnomad4 OTH

AF:

0.198

Alfa

AF:

0.173

Hom.:

1054

Bravo

AF:

0.182

EpiCase

AF:

0.200

EpiControl

AF:

0.204

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jul 31, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 22% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy, Progressive Myoclonus Epilepsy and Abnormal Movements and Neurodegeneration with brain iron accumulation. Number of patients: 20. Only high quality variants are reported. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 04, 2014	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 07, 2017	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Migraine, familial hemiplegic, 2

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -

Alternating hemiplegia of childhood 1

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 09, 2016

This alteration is classified as 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. -

Fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

Developmental and epileptic encephalopathy 98

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

Familial hemiplegic migraine

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

1.8

DANN

Benign

0.81

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over