rs17846713

Positions:

chr1-160130411-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000702.4(ATP1A2):c.1652-11C>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0451 in 1,614,142 control chromosomes in the GnomAD database, including 1,979 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.032 ( 135 hom., cov: 32)

Exomes 𝑓: 0.046 ( 1844 hom. )

Consequence

ATP1A2
NM_000702.4 splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.0006314

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: -0.339

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.71).

BP6

Variant 1-160130411-C-G is Benign according to our data. Variant chr1-160130411-C-G is described in ClinVar as [Benign]. Clinvar id is 256763.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-160130411-C-G is described in Lovd as [Benign]. Variant chr1-160130411-C-G is described in Lovd as [Likely_benign].

BA1

GnomAdExome4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.053 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP1A2	NM_000702.4 linkuse as main transcript	c.1652-11C>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000361216.8
ATP1A2	XM_047421286.1 linkuse as main transcript	c.761-11C>G		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Appris
ATP1A2	ENST00000361216.8 linkuse as main transcript	c.1652-11C>G	splice_polypyrimidine_tract_variant, intron_variant	1	NM_000702.4	P1
ATP1A2	ENST00000392233.7 linkuse as main transcript	c.1652-11C>G	splice_polypyrimidine_tract_variant, intron_variant	5
ATP1A2	ENST00000447527.1 linkuse as main transcript	c.784-11C>G	splice_polypyrimidine_tract_variant, intron_variant	2
ATP1A2	ENST00000472488.5 linkuse as main transcript	n.1755-11C>G	splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant	2

Frequencies

GnomAD3 genomes

AF:

0.0325

AC:

4949

AN:

152166

Hom.:

135

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00893

Gnomad AMI

AF:

0.0230

Gnomad AMR

AF:

0.0295

Gnomad ASJ

AF:

0.0297

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0164

Gnomad FIN

AF:

0.0352

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0513

Gnomad OTH

AF:

0.0278

GnomAD3 exomes

AF:

0.0324

AC:

8156

AN:

251394

Hom.:

196

AF XY:

0.0336

AC XY:

4570

AN XY:

135878

show subpopulations

Gnomad AFR exome

AF:

0.00775

Gnomad AMR exome

AF:

0.0149

Gnomad ASJ exome

AF:

0.0306

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0219

Gnomad FIN exome

AF:

0.0381

Gnomad NFE exome

AF:

0.0483

Gnomad OTH exome

AF:

0.0362

GnomAD4 exome

AF:

0.0464

AC:

67816

AN:

1461858

Hom.:

1844

Cov.:

AF XY:

0.0457

AC XY:

33202

AN XY:

727230

show subpopulations

Gnomad4 AFR exome

AF:

0.00669

Gnomad4 AMR exome

AF:

0.0164

Gnomad4 ASJ exome

AF:

0.0312

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.0217

Gnomad4 FIN exome

AF:

0.0408

Gnomad4 NFE exome

AF:

0.0534

Gnomad4 OTH exome

AF:

0.0415

GnomAD4 genome

AF:

0.0325

AC:

4947

AN:

152284

Hom.:

135

Cov.:

AF XY:

0.0306

AC XY:

2275

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.00890

Gnomad4 AMR

AF:

0.0295

Gnomad4 ASJ

AF:

0.0297

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0164

Gnomad4 FIN

AF:

0.0352

Gnomad4 NFE

AF:

0.0513

Gnomad4 OTH

AF:

0.0275

Alfa

AF:

0.0389

Hom.:

Bravo

AF:

0.0324

Asia WGS

AF:

0.00722

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Migraine, familial hemiplegic, 2

Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -

Alternating hemiplegia of childhood 1

Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -

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

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.71

CADD

Benign

1.2

DANN

Benign

0.70

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00063

dbscSNV1_RF

Benign

0.026

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