1-160130411-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000702.4(ATP1A2):c.1652-11C>G variant causes a 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 intron

Scores

Splicing: ADA: 0.0006314

Clinical Significance

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

Conservation

PhyloP100: -0.339

Publications

6 publications found

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 Gene-Disease associations (from GenCC):

hemiplegic migraine-developmental and epileptic encephalopathy spectrum
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
migraine, familial hemiplegic, 2
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
alternating hemiplegia of childhood 1
Inheritance: AD Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
developmental and epileptic encephalopathy 98
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies
Inheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
alternating hemiplegia of childhood
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
familial or sporadic hemiplegic migraine
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ATP1A2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 256763.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
ATP1A2	NM_000702.4 link	c.1652-11C>G		intron_variant	Intron 12 of 22	ENST00000361216.8	NP_000693.1	P50993A0A0S2Z3W6
ATP1A2	XM_047421286.1 link	c.761-11C>G		intron_variant	Intron 5 of 15		XP_047277242.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
ATP1A2	ENST00000361216.8 link	c.1652-11C>G	intron_variant	Intron 12 of 22	1	NM_000702.4	ENSP00000354490.3	P50993
ATP1A2	ENST00000392233.7 link	c.1652-11C>G	intron_variant	Intron 12 of 22	5		ENSP00000376066.3	B1AKY9
ATP1A2	ENST00000447527.1 link	c.782-11C>G	intron_variant	Intron 5 of 15	2		ENSP00000411705.1	H0Y7C1
ATP1A2	ENST00000472488.5 link	n.1755-11C>G	intron_variant	Intron 12 of 19	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

GnomAD2 exomes

AF:

0.0324

AC:

8156

AN:

251394

AF XY:

0.0336

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 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

African (AFR)

AF:

0.00669

AC:

224

AN:

33480

American (AMR)

AF:

0.0164

AC:

733

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0312

AC:

815

AN:

26134

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39700

South Asian (SAS)

AF:

0.0217

AC:

1874

AN:

86258

European-Finnish (FIN)

AF:

0.0408

AC:

2180

AN:

53410

Middle Eastern (MID)

AF:

0.0215

AC:

124

AN:

5768

European-Non Finnish (NFE)

AF:

0.0534

AC:

59357

AN:

1111990

Other (OTH)

AF:

0.0415

AC:

2506

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

4064

8128

12191

16255

20319

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2184

4368

6552

8736

10920

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0325

AC:

4947

AN:

152284

Hom.:

135

Cov.:

AF XY:

0.0306

AC XY:

2275

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.00890

AC:

370

AN:

41554

American (AMR)

AF:

0.0295

AC:

451

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0297

AC:

103

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.0164

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0352

AC:

373

AN:

10608

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0513

AC:

3487

AN:

68020

Other (OTH)

AF:

0.0275

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

245

490

734

979

1224

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

116

174

232

290

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Migraine, familial hemiplegic, 2

Benign:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Dec 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Alternating hemiplegia of childhood 1

Benign:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Dec 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Benign:1

Dec 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Developmental and epileptic encephalopathy 98

Benign:1

Dec 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Familial hemiplegic migraine

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.71

CADD

Benign

1.2

(source)

DANN

Benign

0.70

PhyloP100

-0.34

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over