chr1-160115831-C-A

Variant names:

• chr1-160115831-C-A
• rs192111085
• NM_000702.4:c.-31C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000702.4(ATP1A2):​c.-31C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000697 in 1,435,490 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: ATP1A2 NM_000702.4 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.535
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).

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.-31C>A		5_prime_UTR	Exon 1 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.-31C>A		5_prime_UTR	Exon 1 of 23	ENSP00000354490.3	P50993
	ATP1A2	ENST00000857225.1		c.-31C>A		5_prime_UTR	Exon 1 of 23	ENSP00000527284.1
	ATP1A2	ENST00000969831.1		c.-31C>A		5_prime_UTR	Exon 1 of 23	ENSP00000639890.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.97e-7 AC: 1 AN: 1435490 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 711222

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33154

American (AMR) AF: 0.00 AC: 0 AN: 40434

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25516

East Asian (EAS) AF: 0.0000259 AC: 1 AN: 38672

South Asian (SAS) AF: 0.00 AC: 0 AN: 81904

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5672

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1099112

Other (OTH) AF: 0.00 AC: 0 AN: 59432

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	2.0
DANN	Benign	0.91
PhyloP100		-0.54
PromoterAI		0.025	Neutral

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: rs192111085; hg19: chr1-160085621;