chr1-160130474-C-T

Position:

• chr1-160130474-C-T

Variant summary

Our verdict is Benign. Variant got -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:15
• Conservation: PhyloP100: -2.54

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BP6: Variant 1-160130474-C-T is Benign according to our data. Variant chr1-160130474-C-T is described in ClinVar as [Benign]. Clinvar id is 128479.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-160130474-C-T is described in Lovd as [Benign]. Variant chr1-160130474-C-T is described in Lovd as [Likely_benign].
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP1A2	NM_000702.4	c.1704C>T	p.Phe568Phe	synonymous_variant	13/23	ENST00000361216.8	NP_000693.1
ATP1A2	XM_047421286.1	c.813C>T	p.Phe271Phe	synonymous_variant	6/16		XP_047277242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP1A2	ENST00000361216.8	c.1704C>T	p.Phe568Phe	synonymous_variant	13/23	1	NM_000702.4	ENSP00000354490.3
ATP1A2	ENST00000392233.7	c.1704C>T	p.Phe568Phe	synonymous_variant	13/23	5		ENSP00000376066.3
ATP1A2	ENST00000447527.1	c.834C>T	p.Phe278Phe	synonymous_variant	6/16	2		ENSP00000411705.1
ATP1A2	ENST00000472488.5	n.1807C>T		non_coding_transcript_exon_variant	13/20	2

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

GnomAD3 exomes AF: 0.0287 AC: 7211 AN: 251478 Hom.: 132 AF XY: 0.0284 AC XY: 3860 AN XY: 135914

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 SAS exome AF: 0.0153

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

Gnomad4 AFR exome AF: 0.0467

Gnomad4 AMR exome AF: 0.0180

Gnomad4 ASJ exome AF: 0.0515

Gnomad4 EAS exome AF: 0.000655

Gnomad4 SAS exome AF: 0.0158

Gnomad4 FIN exome AF: 0.0369

Gnomad4 NFE exome AF: 0.0277

Gnomad4 OTH exome AF: 0.0281

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

Gnomad4 AFR AF: 0.0486

Gnomad4 AMR AF: 0.0260

Gnomad4 ASJ AF: 0.0461

Gnomad4 EAS AF: 0.00174

Gnomad4 SAS AF: 0.0126

Gnomad4 FIN AF: 0.0353

Gnomad4 NFE AF: 0.0319

Gnomad4 OTH AF: 0.0416

Alfa AF: 0.0358 Hom.: 70

Bravo AF: 0.0355

Asia WGS AF: 0.00953 AC: 33 AN: 3478

EpiCase AF: 0.0344

EpiControl AF: 0.0362

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 12, 2012	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. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Migraine, familial hemiplegic, 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Alternating hemiplegia of childhood 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 21, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

Developmental and epileptic encephalopathy 98 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Familial hemiplegic migraine Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	0.94
DANN	Benign	0.69

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

LitVar

Other links and lift over

dbSNP: rs17846714; hg19: chr1-160100264;