rs17846714

Variant names:

• chr1-160130474-C-T
• rs17846714
• NM_000702.4:c.1704C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-160130474-C-T
• chr1-160130474-C-A

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.1704C>T​(p.Phe568Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.028 in 1,614,164 control chromosomes in the GnomAD database, including 749 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.035 (106 hom., cov: 32)
  • Exomes 𝑓: 0.027 (643 hom.)
• Consequence: ATP1A2 NM_000702.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: -2.54
• Publications: 6 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=0.128).
• BP6: Variant 1-160130474-C-T is Benign according to our data. Variant chr1-160130474-C-T is described in ClinVar as Benign. ClinVar VariationId is 128479.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.54 with no splicing effect.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0548 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.1704C>T	p.Phe568Phe	synonymous	Exon 13 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.1704C>T	p.Phe568Phe	synonymous	Exon 13 of 23	ENSP00000354490.3	P50993
	ATP1A2	ENST00000857225.1		c.1728C>T	p.Phe576Phe	synonymous	Exon 13 of 23	ENSP00000527284.1
	ATP1A2	ENST00000969831.1		c.1704C>T	p.Phe568Phe	synonymous	Exon 13 of 23	ENSP00000639890.1

Frequencies

GnomAD3 genomes AF: 0.0348 AC: 5291 AN: 152156 Hom.: 106 Cov.: 32

Gnomad AFR AF: 0.0487

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0260

Gnomad ASJ AF: 0.0461

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.0128

Gnomad FIN AF: 0.0353

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0318

Gnomad OTH AF: 0.0421

GnomAD2 exomes AF: 0.0287 AC: 7211 AN: 251478 AF XY: 0.0284

Gnomad AFR exome AF: 0.0471

Gnomad AMR exome AF: 0.0162

Gnomad ASJ exome AF: 0.0533

Gnomad EAS exome AF: 0.00125

Gnomad FIN exome AF: 0.0365

Gnomad NFE exome AF: 0.0335

Gnomad OTH exome AF: 0.0415

GnomAD4 exome AF: 0.0273 AC: 39864 AN: 1461890 Hom.: 643 Cov.: 33 AF XY: 0.0274 AC XY: 19934 AN XY: 727246

African (AFR) AF: 0.0467 AC: 1563 AN: 33480

American (AMR) AF: 0.0180 AC: 803 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0515 AC: 1346 AN: 26136

East Asian (EAS) AF: 0.000655 AC: 26 AN: 39700

South Asian (SAS) AF: 0.0158 AC: 1361 AN: 86258

European-Finnish (FIN) AF: 0.0369 AC: 1973 AN: 53420

Middle Eastern (MID) AF: 0.0600 AC: 346 AN: 5768

European-Non Finnish (NFE) AF: 0.0277 AC: 30751 AN: 1112008

Other (OTH) AF: 0.0281 AC: 1695 AN: 60396

GnomAD4 genome AF: 0.0348 AC: 5292 AN: 152274 Hom.: 106 Cov.: 32 AF XY: 0.0345 AC XY: 2572 AN XY: 74454

African (AFR) AF: 0.0486 AC: 2020 AN: 41550

American (AMR) AF: 0.0260 AC: 398 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0461 AC: 160 AN: 3472

East Asian (EAS) AF: 0.00174 AC: 9 AN: 5182

South Asian (SAS) AF: 0.0126 AC: 61 AN: 4826

European-Finnish (FIN) AF: 0.0353 AC: 374 AN: 10600

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.0319 AC: 2167 AN: 68018

Other (OTH) AF: 0.0416 AC: 88 AN: 2114

Alfa AF: 0.0338 Hom.: 196

Bravo AF: 0.0355

Asia WGS AF: 0.00953 AC: 33 AN: 3478

EpiCase AF: 0.0344

EpiControl AF: 0.0362

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	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)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	0.94
DANN	Benign	0.69
PhyloP100		-2.5
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: rs17846714; hg19: chr1-160100264;