1-160120891-CCCTT-C

Variant names:

• chr1-160120891-CCCTT-C
• rs373796693
• NM_000702.4:c.13-11_13-8delTCCT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000702.4(ATP1A2):​c.13-11_13-8delTCCT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.805 in 1,573,876 control chromosomes in the GnomAD database, including 516,775 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.73 (42415 hom., cov: 0)
  • Exomes 𝑓: 0.81 (474360 hom.)
• Consequence: ATP1A2 NM_000702.4 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 1.88
• Publications: 5 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 -16 ACMG points.

• BP6: Variant 1-160120891-CCCTT-C is Benign according to our data. Variant chr1-160120891-CCCTT-C is described in ClinVar as Benign. ClinVar VariationId is 166705.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.834 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.13-11_13-8delTCCT		splice_region 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.13-14_13-11delCCTT		intron	N/A	ENSP00000354490.3	P50993
	ATP1A2	ENST00000857225.1		c.13-14_13-11delCCTT		intron	N/A	ENSP00000527284.1
	ATP1A2	ENST00000969831.1		c.13-14_13-11delCCTT		intron	N/A	ENSP00000639890.1

Frequencies

GnomAD3 genomes AF: 0.726 AC: 110308 AN: 151896 Hom.: 42399 Cov.: 0

Gnomad AFR AF: 0.450

Gnomad AMI AF: 0.771

Gnomad AMR AF: 0.846

Gnomad ASJ AF: 0.837

Gnomad EAS AF: 0.844

Gnomad SAS AF: 0.675

Gnomad FIN AF: 0.890

Gnomad MID AF: 0.797

Gnomad NFE AF: 0.829

Gnomad OTH AF: 0.761

GnomAD2 exomes AF: 0.802 AC: 145273 AN: 181048 AF XY: 0.800

Gnomad AFR exome AF: 0.443

Gnomad AMR exome AF: 0.902

Gnomad ASJ exome AF: 0.841

Gnomad EAS exome AF: 0.843

Gnomad FIN exome AF: 0.887

Gnomad NFE exome AF: 0.823

Gnomad OTH exome AF: 0.821

GnomAD4 exome AF: 0.814 AC: 1156790 AN: 1421862 Hom.: 474360 AF XY: 0.811 AC XY: 570564 AN XY: 703848

African (AFR) AF: 0.435 AC: 14063 AN: 32312

American (AMR) AF: 0.897 AC: 34245 AN: 38156

Ashkenazi Jewish (ASJ) AF: 0.844 AC: 21495 AN: 25482

East Asian (EAS) AF: 0.804 AC: 29709 AN: 36940

South Asian (SAS) AF: 0.693 AC: 56382 AN: 81388

European-Finnish (FIN) AF: 0.888 AC: 44998 AN: 50686

Middle Eastern (MID) AF: 0.750 AC: 4232 AN: 5644

European-Non Finnish (NFE) AF: 0.828 AC: 904614 AN: 1092322

Other (OTH) AF: 0.798 AC: 47052 AN: 58932

GnomAD4 genome AF: 0.726 AC: 110354 AN: 152014 Hom.: 42415 Cov.: 0 AF XY: 0.730 AC XY: 54231 AN XY: 74306

African (AFR) AF: 0.449 AC: 18628 AN: 41442

American (AMR) AF: 0.846 AC: 12923 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.837 AC: 2906 AN: 3470

East Asian (EAS) AF: 0.844 AC: 4355 AN: 5158

South Asian (SAS) AF: 0.677 AC: 3269 AN: 4832

European-Finnish (FIN) AF: 0.890 AC: 9412 AN: 10580

Middle Eastern (MID) AF: 0.793 AC: 233 AN: 294

European-Non Finnish (NFE) AF: 0.829 AC: 56318 AN: 67946

Other (OTH) AF: 0.763 AC: 1610 AN: 2110

Alfa AF: 0.781 Hom.: 7935

Bravo AF: 0.720

Asia WGS AF: 0.743 AC: 2585 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	Familial hemiplegic migraine (2)
-	-	1	Alternating hemiplegia of childhood (1)
-	-	1	Alternating hemiplegia of childhood 1 (1)
-	-	1	Developmental and epileptic encephalopathy 98 (1)
-	-	1	Fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies (1)
-	-	1	Migraine, familial hemiplegic, 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.9
Mutation Taster		=100/0	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: rs373796693; hg19: chr1-160090681;