1-160135577-C-T

Position:

• chr1-160135577-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.2259C>T​(p.Ala753=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.113 in 1,614,000 control chromosomes in the GnomAD database, including 10,999 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.093 (873 hom., cov: 32)
  • Exomes 𝑓: 0.11 (10126 hom.)
• Consequence: ATP1A2 NM_000702.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.533

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.28).
• BP6: Variant 1-160135577-C-T is Benign according to our data. Variant chr1-160135577-C-T is described in ClinVar as [Benign]. Clinvar id is 128481.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-160135577-C-T is described in Lovd as [Benign]. Variant chr1-160135577-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.533 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.119 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP1A2	NM_000702.4	c.2259C>T	p.Ala753=	synonymous_variant	16/23	ENST00000361216.8
ATP1A2	XM_047421286.1	c.1368C>T	p.Ala456=	synonymous_variant	9/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP1A2	ENST00000361216.8	c.2259C>T	p.Ala753=	synonymous_variant	16/23	1	NM_000702.4	P1
ATP1A2	ENST00000392233.7	c.2259C>T	p.Ala753=	synonymous_variant	16/23	5
ATP1A2	ENST00000447527.1	c.1392C>T	p.Ala464=	synonymous_variant	9/16	2
ATP1A2	ENST00000472488.5	n.2362C>T		non_coding_transcript_exon_variant	16/20	2

Frequencies

GnomAD3 genomes AF: 0.0925 AC: 14067 AN: 152048 Hom.: 871 Cov.: 32

Gnomad AFR AF: 0.0208

Gnomad AMI AF: 0.102

Gnomad AMR AF: 0.117

Gnomad ASJ AF: 0.107

Gnomad EAS AF: 0.0621

Gnomad SAS AF: 0.0940

Gnomad FIN AF: 0.166

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.121

Gnomad OTH AF: 0.0956

GnomAD3 exomes AF: 0.111 AC: 27911 AN: 251404 Hom.: 1837 AF XY: 0.111 AC XY: 15033 AN XY: 135870

Gnomad AFR exome AF: 0.0203

Gnomad AMR exome AF: 0.133

Gnomad ASJ exome AF: 0.110

Gnomad EAS exome AF: 0.0598

Gnomad SAS exome AF: 0.105

Gnomad FIN exome AF: 0.163

Gnomad NFE exome AF: 0.117

Gnomad OTH exome AF: 0.117

GnomAD4 exome AF: 0.115 AC: 167607 AN: 1461834 Hom.: 10126 Cov.: 34 AF XY: 0.115 AC XY: 83387 AN XY: 727218

Gnomad4 AFR exome AF: 0.0168

Gnomad4 AMR exome AF: 0.132

Gnomad4 ASJ exome AF: 0.109

Gnomad4 EAS exome AF: 0.0488

Gnomad4 SAS exome AF: 0.107

Gnomad4 FIN exome AF: 0.167

Gnomad4 NFE exome AF: 0.118

Gnomad4 OTH exome AF: 0.106

GnomAD4 genome AF: 0.0925 AC: 14076 AN: 152166 Hom.: 873 Cov.: 32 AF XY: 0.0949 AC XY: 7056 AN XY: 74390

Gnomad4 AFR AF: 0.0207

Gnomad4 AMR AF: 0.117

Gnomad4 ASJ AF: 0.107

Gnomad4 EAS AF: 0.0621

Gnomad4 SAS AF: 0.0937

Gnomad4 FIN AF: 0.166

Gnomad4 NFE AF: 0.121

Gnomad4 OTH AF: 0.0965

Alfa AF: 0.108 Hom.: 498

Bravo AF: 0.0830

Asia WGS AF: 0.0860 AC: 301 AN: 3478

EpiCase AF: 0.112

EpiControl AF: 0.106

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jul 15, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 25% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 23. Only high quality variants are reported. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

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	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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 13, 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

clinical testing

GeneDx

Mar 03, 2015

- -

Familial hemiplegic migraine Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.28
CADD	Benign	8.7
DANN	Benign	0.67

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: rs17846715; hg19: chr1-160105367;