rs1046995

chr1-160142951-T-Cchr1-160142951-T-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000702.4(ATP1A2):c.*1629T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.217 in 152,198 control chromosomes in the GnomAD database, including 3,673 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.22 (3673 hom., cov: 32)
  • Exomes 𝑓: 0.18 (0 hom.)
• Consequence: ATP1A2 NM_000702.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.0140

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 1-160142951-T-C is Benign according to our data. Variant chr1-160142951-T-C is described in ClinVar as [Benign]. Clinvar id is 293179.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.269 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP1A2	NM_000702.4	c.*1629T>C		3_prime_UTR_variant	23/23	ENST00000361216.8
ATP1A2	XM_047421286.1	c.*1629T>C		3_prime_UTR_variant	16/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP1A2	ENST00000361216.8	c.*1629T>C		3_prime_UTR_variant	23/23	1	NM_000702.4	P1
ATP1A2	ENST00000447527.1	c.*1629T>C		3_prime_UTR_variant	16/16	2

Frequencies

GnomAD3 genomes AF: 0.217 AC: 33043 AN: 152060 Hom.: 3674 Cov.: 32

Gnomad AFR AF: 0.253

Gnomad AMI AF: 0.261

Gnomad AMR AF: 0.161

Gnomad ASJ AF: 0.206

Gnomad EAS AF: 0.155

Gnomad SAS AF: 0.283

Gnomad FIN AF: 0.152

Gnomad MID AF: 0.171

Gnomad NFE AF: 0.219

Gnomad OTH AF: 0.218

GnomAD4 exome AF: 0.182 AC: 4 AN: 22 Hom.: 0 Cov.: 0 AF XY: 0.214 AC XY: 3 AN XY: 14

Gnomad4 ASJ exome AF: 0.500

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.167

GnomAD4 genome AF: 0.217 AC: 33043 AN: 152176 Hom.: 3673 Cov.: 32 AF XY: 0.214 AC XY: 15926 AN XY: 74400

Gnomad4 AFR AF: 0.252

Gnomad4 AMR AF: 0.161

Gnomad4 ASJ AF: 0.206

Gnomad4 EAS AF: 0.155

Gnomad4 SAS AF: 0.282

Gnomad4 FIN AF: 0.152

Gnomad4 NFE AF: 0.219

Gnomad4 OTH AF: 0.216

Alfa AF: 0.213 Hom.: 4395

Bravo AF: 0.216

Asia WGS AF: 0.209 AC: 726 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

Migraine, familial hemiplegic, 2 Benign:1

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. -

Alternating hemiplegia of childhood 1 Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	1.3
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: rs1046995; hg19: chr1-160112741;