NM_000702.4:c.495+81T>A

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.495+81T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.351 in 1,578,876 control chromosomes in the GnomAD database, including 99,535 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.40 ( 12348 hom., cov: 32)
Exomes 𝑓: 0.35 ( 87187 hom. )

Consequence

ATP1A2
NM_000702.4 intron

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 2.24

Publications

13 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

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=-0.82).
BP6
Variant 1-160124137-T-A is Benign according to our data. Variant chr1-160124137-T-A is described in ClinVar as Benign. ClinVar VariationId is 670754.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.472 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ATP1A2NM_000702.4 linkc.495+81T>A intron_variant Intron 5 of 22 ENST00000361216.8 NP_000693.1 P50993A0A0S2Z3W6

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ATP1A2ENST00000361216.8 linkc.495+81T>A intron_variant Intron 5 of 22 1 NM_000702.4 ENSP00000354490.3 P50993
ATP1A2ENST00000392233.7 linkc.495+81T>A intron_variant Intron 5 of 22 5 ENSP00000376066.3 B1AKY9
ATP1A2ENST00000468587.1 linkn.99+81T>A intron_variant Intron 1 of 2 2
ATP1A2ENST00000472488.5 linkn.598+81T>A intron_variant Intron 5 of 19 2

Frequencies

GnomAD3 genomes
AF:
0.395
AC:
60076
AN:
151954
Hom.:
12346
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.478
Gnomad AMI
AF:
0.310
Gnomad AMR
AF:
0.459
Gnomad ASJ
AF:
0.390
Gnomad EAS
AF:
0.466
Gnomad SAS
AF:
0.250
Gnomad FIN
AF:
0.341
Gnomad MID
AF:
0.494
Gnomad NFE
AF:
0.345
Gnomad OTH
AF:
0.404
GnomAD4 exome
AF:
0.346
AC:
493292
AN:
1426804
Hom.:
87187
Cov.:
29
AF XY:
0.342
AC XY:
243003
AN XY:
709690
show subpopulations
African (AFR)
AF:
0.483
AC:
15855
AN:
32802
American (AMR)
AF:
0.455
AC:
18929
AN:
41600
Ashkenazi Jewish (ASJ)
AF:
0.401
AC:
10329
AN:
25734
East Asian (EAS)
AF:
0.460
AC:
18091
AN:
39336
South Asian (SAS)
AF:
0.245
AC:
20662
AN:
84366
European-Finnish (FIN)
AF:
0.348
AC:
18206
AN:
52384
Middle Eastern (MID)
AF:
0.408
AC:
2111
AN:
5168
European-Non Finnish (NFE)
AF:
0.338
AC:
367644
AN:
1086186
Other (OTH)
AF:
0.362
AC:
21465
AN:
59228
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.501
Heterozygous variant carriers
0
18156
36312
54468
72624
90780
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
11918
23836
35754
47672
59590
<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:
0.395
AC:
60121
AN:
152072
Hom.:
12348
Cov.:
32
AF XY:
0.395
AC XY:
29356
AN XY:
74358
show subpopulations
African (AFR)
AF:
0.478
AC:
19812
AN:
41452
American (AMR)
AF:
0.459
AC:
7009
AN:
15286
Ashkenazi Jewish (ASJ)
AF:
0.390
AC:
1354
AN:
3468
East Asian (EAS)
AF:
0.466
AC:
2405
AN:
5166
South Asian (SAS)
AF:
0.251
AC:
1212
AN:
4828
European-Finnish (FIN)
AF:
0.341
AC:
3609
AN:
10590
Middle Eastern (MID)
AF:
0.490
AC:
143
AN:
292
European-Non Finnish (NFE)
AF:
0.345
AC:
23432
AN:
67964
Other (OTH)
AF:
0.408
AC:
862
AN:
2114
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.503
Heterozygous variant carriers
0
1867
3733
5600
7466
9333
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
558
1116
1674
2232
2790
<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:
0.373
Hom.:
1404
Bravo
AF:
0.414
Asia WGS
AF:
0.384
AC:
1334
AN:
3478

ClinVar

Significance: Benign
Submissions summary: Benign:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:2
Jun 18, 2018
GeneDx
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-
Breakthrough Genomics, Breakthrough Genomics
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:not provided

- -

not specified Benign:1
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 22% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 20. Only high quality variants are reported. -

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

- -

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
Jul 14, 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
BayesDel_noAF
Benign
-0.82
CADD
Benign
8.0
DANN
Benign
0.40
PhyloP100
2.2
Mutation Taster
=100/0
polymorphism (auto)

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

Other links and lift over

dbSNP: rs2854248; hg19: chr1-160093927; COSMIC: COSV63406380; COSMIC: COSV63406380; API