rs372906753

Variant names:

• chr1-160115953-G-T
• rs372906753
• NM_000702.4:c.12+80G>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS1

The NM_000702.4(ATP1A2):​c.12+80G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000517 in 1,557,764 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0029 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00026 (1 hom.)
• Consequence: ATP1A2 NM_000702.4 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.282
• Publications: 0 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: G2P, Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• alternating hemiplegia of childhood 1

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
• developmental and epileptic encephalopathy 98

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 1-160115953-G-T is Benign according to our data. Variant chr1-160115953-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1213194.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00292 (444/152290) while in subpopulation AFR AF = 0.0101 (420/41552). AF 95% confidence interval is 0.00931. There are 1 homozygotes in GnomAd4. There are 228 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.12+80G>T		intron	N/A	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.12+80G>T		intron	N/A	ENSP00000354490.3	P50993
	ATP1A2	ENST00000857225.1		c.12+80G>T		intron	N/A	ENSP00000527284.1
	ATP1A2	ENST00000969831.1		c.12+80G>T		intron	N/A	ENSP00000639890.1

Frequencies

GnomAD3 genomes AF: 0.00292 AC: 444 AN: 152172 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00287

GnomAD4 exome AF: 0.000257 AC: 361 AN: 1405474 Hom.: 1 AF XY: 0.000222 AC XY: 154 AN XY: 694918

African (AFR) AF: 0.00879 AC: 284 AN: 32302

American (AMR) AF: 0.000759 AC: 28 AN: 36878

Ashkenazi Jewish (ASJ) AF: 0.0000793 AC: 2 AN: 25218

East Asian (EAS) AF: 0.00 AC: 0 AN: 37284

South Asian (SAS) AF: 0.0000250 AC: 2 AN: 80056

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50248

Middle Eastern (MID) AF: 0.000353 AC: 2 AN: 5658

European-Non Finnish (NFE) AF: 0.0000102 AC: 11 AN: 1079436

Other (OTH) AF: 0.000548 AC: 32 AN: 58394

GnomAD4 genome AF: 0.00292 AC: 444 AN: 152290 Hom.: 1 Cov.: 32 AF XY: 0.00306 AC XY: 228 AN XY: 74466

African (AFR) AF: 0.0101 AC: 420 AN: 41552

American (AMR) AF: 0.00111 AC: 17 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68018

Other (OTH) AF: 0.00284 AC: 6 AN: 2116

Alfa AF: 0.00236 Hom.: 0

Bravo AF: 0.00318

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	6.3
DANN	Benign	0.80
PhyloP100		-0.28
PromoterAI		0.024	Neutral
Mutation Taster		=100/0	polymorphism

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: rs372906753; hg19: chr1-160085743;