1-160124137-T-A

Variant names:

• chr1-160124137-T-A
• rs2854248
• NM_000702.4:c.495+81T>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 2.24
• Publications: 13 publications found

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), ClinGen, Ambry Genetics, G2P
• 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, Labcorp Genetics (formerly Invitae), G2P
• alternating hemiplegia of childhood

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial or sporadic hemiplegic migraine

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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.

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.495+81T>A		intron	N/A	NP_000693.1	P50993

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP1A2	ENST00000361216.8	TSL:1 MANE Select	c.495+81T>A		intron	N/A	ENSP00000354490.3	P50993
	ATP1A2	ENST00000857225.1		c.495+81T>A		intron	N/A	ENSP00000527284.1
	ATP1A2	ENST00000969831.1		c.495+81T>A		intron	N/A	ENSP00000639890.1

Frequencies

GnomAD3 genomes AF: 0.395 AC: 60076 AN: 151954 Hom.: 12346 Cov.: 32

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

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

GnomAD4 genome AF: 0.395 AC: 60121 AN: 152072 Hom.: 12348 Cov.: 32 AF XY: 0.395 AC XY: 29356 AN XY: 74358

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

Alfa AF: 0.373 Hom.: 1404

Bravo AF: 0.414

Asia WGS AF: 0.384 AC: 1334 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Alternating hemiplegia of childhood 1 (1)
-	-	1	Developmental and epileptic encephalopathy 98 (1)
-	-	1	Fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies (1)
-	-	1	Migraine, familial hemiplegic, 2 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2854248;

hg19: chr1-160093927;

COSMIC: COSV63406380;

COSMIC: COSV63406380;