1-160142348-A-G

Variant names:

• chr1-160142348-A-G
• rs2070704
• NM_000702.4:c.*1026A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000702.4(ATP1A2):​c.*1026A>G 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 151,994 control chromosomes in the GnomAD database, including 3,678 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (3676 hom., cov: 32)
  • Exomes 𝑓: 0.26 (2 hom.)
• Consequence: ATP1A2 NM_000702.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.871
• Publications: 14 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
• fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies

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

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

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 1-160142348-A-G is Benign according to our data. Variant chr1-160142348-A-G is described in ClinVar as Benign. ClinVar VariationId is 293160.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.27 is higher than 0.05.

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.*1026A>G		3_prime_UTR	Exon 23 of 23	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.*1026A>G		3_prime_UTR	Exon 23 of 23	ENSP00000354490.3	P50993
	ATP1A2	ENST00000857225.1		c.*1026A>G		3_prime_UTR	Exon 23 of 23	ENSP00000527284.1
	ATP1A2	ENST00000969831.1		c.*1026A>G		3_prime_UTR	Exon 23 of 23	ENSP00000639890.1

Frequencies

GnomAD3 genomes AF: 0.217 AC: 33015 AN: 151834 Hom.: 3677 Cov.: 32

Gnomad AFR AF: 0.253

Gnomad AMI AF: 0.262

Gnomad AMR AF: 0.161

Gnomad ASJ AF: 0.206

Gnomad EAS AF: 0.154

Gnomad SAS AF: 0.283

Gnomad FIN AF: 0.153

Gnomad MID AF: 0.171

Gnomad NFE AF: 0.219

Gnomad OTH AF: 0.219

GnomAD4 exome AF: 0.262 AC: 11 AN: 42 Hom.: 2 Cov.: 0 AF XY: 0.294 AC XY: 10 AN XY: 34

African (AFR) AF: 0.500 AC: 1 AN: 2

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.278 AC: 10 AN: 36

Other (OTH) AF: 0.00 AC: 0 AN: 2

GnomAD4 genome AF: 0.217 AC: 33016 AN: 151952 Hom.: 3676 Cov.: 32 AF XY: 0.214 AC XY: 15917 AN XY: 74258

African (AFR) AF: 0.252 AC: 10453 AN: 41422

American (AMR) AF: 0.161 AC: 2459 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.206 AC: 714 AN: 3466

East Asian (EAS) AF: 0.155 AC: 797 AN: 5158

South Asian (SAS) AF: 0.282 AC: 1355 AN: 4802

European-Finnish (FIN) AF: 0.153 AC: 1612 AN: 10548

Middle Eastern (MID) AF: 0.180 AC: 53 AN: 294

European-Non Finnish (NFE) AF: 0.219 AC: 14877 AN: 67962

Other (OTH) AF: 0.217 AC: 458 AN: 2112

Alfa AF: 0.212 Hom.: 5050

Bravo AF: 0.216

Asia WGS AF: 0.210 AC: 728 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Alternating hemiplegia of childhood 1 (2)
-	-	2	Migraine, familial hemiplegic, 2 (2)
-	-	2	not provided (2)
-	-	1	Developmental and epileptic encephalopathy 98 (1)
-	-	1	Fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	5.9
DANN	Benign	0.42
PhyloP100		0.87
Mutation Taster		=99/1	polymorphism (auto)

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: rs2070704; hg19: chr1-160112138;