rs55858252

Variant names:

• chr1-160120918-T-A
• rs55858252
• NM_000702.4:c.25T>A
• ATP1A2 p.Tyr9Asn

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BS1 BS2

The NM_000702.4(ATP1A2):​c.25T>A​(p.Tyr9Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00303 in 1,596,846 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y9C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0021 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0031 (9 hom.)
• Consequence: ATP1A2 NM_000702.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:14
• Conservation: PhyloP100: 1.67
• Publications: 7 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 -12 ACMG points.

• PP2: Missense variant in the ATP1A2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 63 curated pathogenic missense variants (we use a threshold of 10). The gene has 10 curated benign missense variants. Gene score misZ: 4.7713 (above the threshold of 3.09). Trascript score misZ: 6.824 (above the threshold of 3.09). GenCC associations: The gene is linked to migraine, familial hemiplegic, 2, familial or sporadic hemiplegic migraine, alternating hemiplegia of childhood 1, alternating hemiplegia of childhood, fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies, developmental and epileptic encephalopathy 98, hemiplegic migraine-developmental and epileptic encephalopathy spectrum.
• BP4: Computational evidence support a benign effect (MetaRNN=0.012802213).
• BP6: Variant 1-160120918-T-A is Benign according to our data. Variant chr1-160120918-T-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 204881.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0021 (319/152130) while in subpopulation NFE AF = 0.00381 (259/68004). AF 95% confidence interval is 0.00343. There are 1 homozygotes in GnomAd4. There are 146 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 9 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.25T>A	p.Tyr9Asn	missense	Exon 2 of 23	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.25T>A	p.Tyr9Asn	missense	Exon 2 of 23	ENSP00000354490.3	P50993
	ATP1A2	ENST00000857225.1		c.25T>A	p.Tyr9Asn	missense	Exon 2 of 23	ENSP00000527284.1
	ATP1A2	ENST00000969831.1		c.25T>A	p.Tyr9Asn	missense	Exon 2 of 23	ENSP00000639890.1

Frequencies

GnomAD3 genomes AF: 0.00210 AC: 319 AN: 152012 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000652

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00138

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000623

Gnomad FIN AF: 0.0000947

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00381

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00170 AC: 365 AN: 214772 AF XY: 0.00174

Gnomad AFR exome AF: 0.000754

Gnomad AMR exome AF: 0.000948

Gnomad ASJ exome AF: 0.000106

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000214

Gnomad NFE exome AF: 0.00314

Gnomad OTH exome AF: 0.000922

GnomAD4 exome AF: 0.00313 AC: 4523 AN: 1444716 Hom.: 9 Cov.: 34 AF XY: 0.00305 AC XY: 2191 AN XY: 717300

African (AFR) AF: 0.000485 AC: 16 AN: 32996

American (AMR) AF: 0.000839 AC: 35 AN: 41696

Ashkenazi Jewish (ASJ) AF: 0.0000387 AC: 1 AN: 25856

East Asian (EAS) AF: 0.0000260 AC: 1 AN: 38498

South Asian (SAS) AF: 0.000727 AC: 61 AN: 83914

European-Finnish (FIN) AF: 0.000172 AC: 9 AN: 52190

Middle Eastern (MID) AF: 0.000348 AC: 2 AN: 5744

European-Non Finnish (NFE) AF: 0.00379 AC: 4187 AN: 1104110

Other (OTH) AF: 0.00353 AC: 211 AN: 59712

GnomAD4 genome AF: 0.00210 AC: 319 AN: 152130 Hom.: 1 Cov.: 33 AF XY: 0.00196 AC XY: 146 AN XY: 74354

African (AFR) AF: 0.000651 AC: 27 AN: 41504

American (AMR) AF: 0.00137 AC: 21 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000624 AC: 3 AN: 4810

European-Finnish (FIN) AF: 0.0000947 AC: 1 AN: 10562

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00381 AC: 259 AN: 68004

Other (OTH) AF: 0.00284 AC: 6 AN: 2110

Alfa AF: 0.00308 Hom.: 0

Bravo AF: 0.00226

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	4	not provided (5)
-	-	2	Alternating hemiplegia of childhood 1 (2)
-	-	2	Migraine, familial hemiplegic, 2 (2)
-	-	2	not specified (2)
-	-	1	Developmental and epileptic encephalopathy 98 (1)
-	-	1	Familial hemiplegic migraine (1)
-	-	1	Fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	23
DANN	Benign	0.94
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.028
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.084	D
MetaRNN	Benign	0.013	T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	1.1	L
PhyloP100		1.7
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	0.20	N
REVEL	Benign	0.28
Sift	Benign	0.34	T
Sift4G	Benign	0.24	T
Varity_R		0.12
gMVP		0.79
Mutation Taster		=83/17	polymorphism

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: rs55858252; hg19: chr1-160090708;