rs1063125

Variant names:

• chr1-160128753-G-A
• rs1063125
• NM_000702.4:c.1119G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-160128753-G-A
• chr1-160128753-G-C
• chr1-160128753-G-T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000702.4(ATP1A2):​c.1119G>A​(p.Ser373Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.194 in 1,613,918 control chromosomes in the GnomAD database, including 31,710 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (2807 hom., cov: 31)
  • Exomes 𝑓: 0.19 (28903 hom.)
• Consequence: ATP1A2 NM_000702.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: -6.55
• Publications: 21 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), 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

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.103).
• BP6: Variant 1-160128753-G-A is Benign according to our data. Variant chr1-160128753-G-A is described in ClinVar as Benign. ClinVar VariationId is 128477.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-6.55 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.314 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.1119G>A	p.Ser373Ser	synonymous	Exon 9 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.1119G>A	p.Ser373Ser	synonymous	Exon 9 of 23	ENSP00000354490.3	P50993
	ATP1A2	ENST00000857225.1		c.1119G>A	p.Ser373Ser	synonymous	Exon 9 of 23	ENSP00000527284.1
	ATP1A2	ENST00000969831.1		c.1119G>A	p.Ser373Ser	synonymous	Exon 9 of 23	ENSP00000639890.1

Frequencies

GnomAD3 genomes AF: 0.188 AC: 28522 AN: 151908 Hom.: 2798 Cov.: 31

Gnomad AFR AF: 0.192

Gnomad AMI AF: 0.237

Gnomad AMR AF: 0.141

Gnomad ASJ AF: 0.181

Gnomad EAS AF: 0.159

Gnomad SAS AF: 0.328

Gnomad FIN AF: 0.139

Gnomad MID AF: 0.196

Gnomad NFE AF: 0.195

Gnomad OTH AF: 0.200

GnomAD2 exomes AF: 0.190 AC: 47782 AN: 251460 AF XY: 0.199

Gnomad AFR exome AF: 0.186

Gnomad AMR exome AF: 0.0890

Gnomad ASJ exome AF: 0.178

Gnomad EAS exome AF: 0.160

Gnomad FIN exome AF: 0.141

Gnomad NFE exome AF: 0.200

Gnomad OTH exome AF: 0.197

GnomAD4 exome AF: 0.195 AC: 284353 AN: 1461892 Hom.: 28903 Cov.: 35 AF XY: 0.199 AC XY: 144823 AN XY: 727246

African (AFR) AF: 0.188 AC: 6309 AN: 33480

American (AMR) AF: 0.0934 AC: 4179 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.178 AC: 4640 AN: 26136

East Asian (EAS) AF: 0.195 AC: 7746 AN: 39700

South Asian (SAS) AF: 0.317 AC: 27318 AN: 86258

European-Finnish (FIN) AF: 0.141 AC: 7558 AN: 53420

Middle Eastern (MID) AF: 0.246 AC: 1417 AN: 5768

European-Non Finnish (NFE) AF: 0.192 AC: 213451 AN: 1112010

Other (OTH) AF: 0.194 AC: 11735 AN: 60396

GnomAD4 genome AF: 0.188 AC: 28552 AN: 152026 Hom.: 2807 Cov.: 31 AF XY: 0.187 AC XY: 13905 AN XY: 74318

African (AFR) AF: 0.192 AC: 7960 AN: 41470

American (AMR) AF: 0.141 AC: 2156 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.181 AC: 630 AN: 3472

East Asian (EAS) AF: 0.160 AC: 822 AN: 5152

South Asian (SAS) AF: 0.327 AC: 1573 AN: 4806

European-Finnish (FIN) AF: 0.139 AC: 1475 AN: 10588

Middle Eastern (MID) AF: 0.204 AC: 60 AN: 294

European-Non Finnish (NFE) AF: 0.195 AC: 13243 AN: 67956

Other (OTH) AF: 0.198 AC: 417 AN: 2110

Alfa AF: 0.173 Hom.: 1054

Bravo AF: 0.182

EpiCase AF: 0.200

EpiControl AF: 0.204

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	2	Alternating hemiplegia of childhood 1 (2)
-	-	2	Migraine, familial hemiplegic, 2 (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
BayesDel_noAF	Benign	-0.80
CADD	Benign	1.8
DANN	Benign	0.81
PhyloP100		-6.5
Mutation Taster		=99/1	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

Other links and lift over

dbSNP: rs1063125; hg19: chr1-160098543; COSMIC: COSV63402896; COSMIC: COSV63402896;