rs397775888

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_000702.4(ATP1A2):c.2841-20dupC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.133 in 1,610,610 control chromosomes in the GnomAD database, including 14,940 homozygotes. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.13 ( 1371 hom., cov: 30)

Exomes 𝑓: 0.13 ( 13569 hom. )

Consequence

ATP1A2
NM_000702.4 intron

Scores

Not classified

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.261

Publications

0 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 -16 ACMG points.

BP6

Variant 1-160139618-A-AC is Benign according to our data. Variant chr1-160139618-A-AC is described in ClinVar as Benign. ClinVar VariationId is 204875.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.138 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP1A2	NM_000702.4 link	c.2841-20dupC		intron_variant	Intron 20 of 22	ENST00000361216.8	NP_000693.1	P50993A0A0S2Z3W6
ATP1A2	XM_047421286.1 link	c.1950-20dupC		intron_variant	Intron 13 of 15		XP_047277242.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
ATP1A2	ENST00000361216.8 link	c.2841-22_2841-21insC	intron_variant	Intron 20 of 22	1	NM_000702.4	ENSP00000354490.3	P50993
ATP1A2	ENST00000392233.7 link	c.2841-22_2841-21insC	intron_variant	Intron 20 of 22	5		ENSP00000376066.3	B1AKY9
ATP1A2	ENST00000447527.1 link	c.1920-22_1920-21insC	intron_variant	Intron 13 of 15	2		ENSP00000411705.1	H0Y7C1
ATP1A2	ENST00000463989.1 link	n.177-22_177-21insC	intron_variant	Intron 2 of 3	2

Frequencies

GnomAD3 genomes

AF:

0.131

AC:

19831

AN:

151786

Hom.:

1369

Cov.:

show subpopulations

Gnomad AFR

AF:

0.113

Gnomad AMI

AF:

0.103

Gnomad AMR

AF:

0.135

Gnomad ASJ

AF:

0.106

Gnomad EAS

AF:

0.0641

Gnomad SAS

AF:

0.105

Gnomad FIN

AF:

0.187

Gnomad MID

AF:

0.0665

Gnomad NFE

AF:

0.141

Gnomad OTH

AF:

0.127

GnomAD2 exomes

AF:

0.131

AC:

32802

AN:

251090

AF XY:

0.129

show subpopulations

Gnomad AFR exome

AF:

0.113

Gnomad AMR exome

AF:

0.143

Gnomad ASJ exome

AF:

0.108

Gnomad EAS exome

AF:

0.0608

Gnomad FIN exome

AF:

0.183

Gnomad NFE exome

AF:

0.137

Gnomad OTH exome

AF:

0.133

GnomAD4 exome

AF:

0.133

AC:

194623

AN:

1458706

Hom.:

13569

Cov.:

AF XY:

0.133

AC XY:

96650

AN XY:

725876

show subpopulations

African (AFR)

AF:

0.109

AC:

3637

AN:

33436

American (AMR)

AF:

0.143

AC:

6374

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.107

AC:

2803

AN:

26122

East Asian (EAS)

AF:

0.0497

AC:

1971

AN:

39684

South Asian (SAS)

AF:

0.117

AC:

10050

AN:

86208

European-Finnish (FIN)

AF:

0.189

AC:

10036

AN:

52984

Middle Eastern (MID)

AF:

0.0748

AC:

431

AN:

5764

European-Non Finnish (NFE)

AF:

0.137

AC:

151843

AN:

1109486

Other (OTH)

AF:

0.124

AC:

7478

AN:

60302

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

7836

15672

23508

31344

39180

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5338

10676

16014

21352

26690

<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:

0.131

AC:

19841

AN:

151904

Hom.:

1371

Cov.:

AF XY:

0.132

AC XY:

9816

AN XY:

74228

show subpopulations

African (AFR)

AF:

0.113

AC:

4670

AN:

41414

American (AMR)

AF:

0.136

AC:

2069

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.106

AC:

368

AN:

3458

East Asian (EAS)

AF:

0.0641

AC:

331

AN:

5164

South Asian (SAS)

AF:

0.104

AC:

500

AN:

4806

European-Finnish (FIN)

AF:

0.187

AC:

1975

AN:

10554

Middle Eastern (MID)

AF:

0.0714

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.141

AC:

9545

AN:

67932

Other (OTH)

AF:

0.127

AC:

268

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

878

1756

2635

3513

4391

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

220

440

660

880

1100

<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:

0.139

Hom.:

350

Bravo

AF:

0.122

Asia WGS

AF:

0.0950

AC:

332

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 25% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 23. Only high quality variants are reported. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 22, 2013

GeneDx

Significance:Benign

Review Status:flagged submission

Collection Method:clinical testing

The variant is found in EPILEPSY panel(s). -

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

- -

not provided

Benign:1

Jun 29, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Migraine, familial hemiplegic, 2

Benign:1

Dec 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Alternating hemiplegia of childhood 1

Benign:1

Dec 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.26

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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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