rs41288127

Positions:

• chr1-160139998-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000702.4(ATP1A2):​c.3034+14C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.133 in 1,612,062 control chromosomes in the GnomAD database, including 14,908 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1360 hom., cov: 31)
  • Exomes 𝑓: 0.13 (13548 hom.)
• Consequence: ATP1A2 NM_000702.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.134

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 1-160139998-C-T is Benign according to our data. Variant chr1-160139998-C-T is described in ClinVar as [Benign]. Clinvar id is 256764.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-160139998-C-T is described in Lovd as [Benign]. Variant chr1-160139998-C-T is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.138 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP1A2	NM_000702.4	c.3034+14C>T		intron_variant		ENST00000361216.8	NP_000693.1
ATP1A2	XM_047421286.1	c.2143+14C>T		intron_variant			XP_047277242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP1A2	ENST00000361216.8	c.3034+14C>T		intron_variant		1	NM_000702.4	ENSP00000354490	P1

Frequencies

GnomAD3 genomes AF: 0.130 AC: 19735 AN: 151930 Hom.: 1358 Cov.: 31

Gnomad AFR AF: 0.113

Gnomad AMI AF: 0.103

Gnomad AMR AF: 0.135

Gnomad ASJ AF: 0.104

Gnomad EAS AF: 0.0625

Gnomad SAS AF: 0.104

Gnomad FIN AF: 0.185

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.140

Gnomad OTH AF: 0.125

GnomAD3 exomes AF: 0.130 AC: 32641 AN: 250404 Hom.: 2353 AF XY: 0.129 AC XY: 17463 AN XY: 135436

Gnomad AFR exome AF: 0.113

Gnomad AMR exome AF: 0.142

Gnomad ASJ exome AF: 0.107

Gnomad EAS exome AF: 0.0608

Gnomad SAS exome AF: 0.114

Gnomad FIN exome AF: 0.183

Gnomad NFE exome AF: 0.137

Gnomad OTH exome AF: 0.133

GnomAD4 exome AF: 0.133 AC: 194626 AN: 1460014 Hom.: 13548 Cov.: 33 AF XY: 0.133 AC XY: 96623 AN XY: 726416

Gnomad4 AFR exome AF: 0.109

Gnomad4 AMR exome AF: 0.142

Gnomad4 ASJ exome AF: 0.106

Gnomad4 EAS exome AF: 0.0493

Gnomad4 SAS exome AF: 0.117

Gnomad4 FIN exome AF: 0.190

Gnomad4 NFE exome AF: 0.137

Gnomad4 OTH exome AF: 0.124

GnomAD4 genome AF: 0.130 AC: 19745 AN: 152048 Hom.: 1360 Cov.: 31 AF XY: 0.131 AC XY: 9748 AN XY: 74324

Gnomad4 AFR AF: 0.112

Gnomad4 AMR AF: 0.135

Gnomad4 ASJ AF: 0.104

Gnomad4 EAS AF: 0.0624

Gnomad4 SAS AF: 0.104

Gnomad4 FIN AF: 0.185

Gnomad4 NFE AF: 0.140

Gnomad4 OTH AF: 0.125

Alfa AF: 0.142 Hom.: 305

Bravo AF: 0.122

Asia WGS AF: 0.0950 AC: 332 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

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 27% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 25. Only high quality variants are reported. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Migraine, familial hemiplegic, 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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	- -

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 13, 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. -

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

- -

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	-0.84
CADD	Benign	1.0
DANN	Benign	0.59

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: rs41288127; hg19: chr1-160109788;