rs3747626

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBS1BS2

The NM_000702.4(ATP1A2):c.2563+4C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000631 in 1,613,950 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.00086 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00061 ( 4 hom. )

Consequence

ATP1A2
NM_000702.4 splice_region, intron

Scores

Splicing: ADA: 0.007580

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -0.290

Publications

3 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, ClinGen
alternating hemiplegia of childhood 1
Inheritance: AD Classification: STRONG, LIMITED Submitted by: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)
developmental and epileptic encephalopathy 98
Inheritance: AD 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 -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.38).

BP6

Variant 1-160136374-C-T is Benign according to our data. Variant chr1-160136374-C-T is described in ClinVar as Benign. ClinVar VariationId is 128483.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00086 (131/152288) while in subpopulation EAS AF = 0.0124 (64/5162). AF 95% confidence interval is 0.00996. There are 1 homozygotes in GnomAd4. There are 89 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 4 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000702.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP1A2	NM_000702.4	MANE Select	c.2563+4C>T		splice_region intron	N/A	NP_000693.1	P50993

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ATP1A2	ENST00000361216.8	TSL:1 MANE Select	c.2563+4C>T	splice_region intron	N/A	ENSP00000354490.3	P50993
ATP1A2	ENST00000857225.1		c.2587+4C>T	splice_region intron	N/A	ENSP00000527284.1
ATP1A2	ENST00000969831.1		c.2563+4C>T	splice_region intron	N/A	ENSP00000639890.1

Frequencies

GnomAD3 genomes

AF:

0.000867

AC:

132

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00374

Gnomad EAS

AF:

0.0124

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00348

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.00168

AC:

421

AN:

250812

AF XY:

0.00167

show subpopulations

Gnomad AFR exome

AF:

0.0000619

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00526

Gnomad EAS exome

AF:

0.0136

Gnomad FIN exome

AF:

0.00382

Gnomad NFE exome

AF:

0.000176

Gnomad OTH exome

AF:

0.000653

GnomAD4 exome

AF:

0.000608

AC:

888

AN:

1461662

Hom.:

Cov.:

AF XY:

0.000649

AC XY:

472

AN XY:

727128

show subpopulations

African (AFR)

AF:

0.000119

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00524

AC:

137

AN:

26136

East Asian (EAS)

AF:

0.00955

AC:

379

AN:

39700

South Asian (SAS)

AF:

0.000638

AC:

AN:

86238

European-Finnish (FIN)

AF:

0.00295

AC:

157

AN:

53226

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.0000800

AC:

AN:

1112006

Other (OTH)

AF:

0.00111

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

118

176

235

294

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.000860

AC:

131

AN:

152288

Hom.:

Cov.:

AF XY:

0.00120

AC XY:

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.000144

AC:

AN:

41566

American (AMR)

AF:

0.0000653

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00374

AC:

AN:

3472

East Asian (EAS)

AF:

0.0124

AC:

AN:

5162

South Asian (SAS)

AF:

0.000621

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00348

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

68012

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.000443

Hom.:

Bravo

AF:

0.00100

Asia WGS

AF:

0.00375

AC:

AN:

3478

EpiCase

AF:

0.000327

EpiControl

AF:

0.000119

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Alternating hemiplegia of childhood 1 (2)

Migraine, familial hemiplegic, 2 (2)

not specified (2)

Developmental and epileptic encephalopathy 98 (1)

Familial hemiplegic migraine (1)

Fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies (1)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Benign

0.82

PhyloP100

-0.29

Mutation Taster

=56/44

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0076

dbscSNV1_RF

Benign

0.062

SpliceAI score (max)

0.18

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over