ATP8A2

Gene Facts

• HGNC Symbol: ATP8A2 (HGNC:13533)
• HGNC Name: ATPase phospholipid transporting 8A2
• Gene type: protein-coding gene
• Locus type: gene with protein product
• Previous symbols: No previous names found
• Alias symbols: ATPIB, ML-1
• %HI: 24.95
• pLI: 0
• LOEUF: 0.73
• Cytoband: 13q12.13
• Genomic Coordinates:

  GRCh37/hg19:	chr13:25946112-26599989
  GRCh38/hg38:	chr13:25371974-26025851

• MANE Select Transcript: NM_016529.6 ENST00000381655.7
• Function: Catalytic component of a P4-ATPase flippase complex which catalyzes the hydrolysis of ATP coupled to the transport of aminophospholipids from the outer to the inner leaflet of various membranes and ensures the maintenance of asymmetric distribution of phospholipids (By similarity). Able to translocate phosphatidylserine, but not phosphatidylcholine (PubMed:34403372). Phospholipid translocation seems also to be implicated in vesicle formation and in uptake of lipid signaling molecules (By similar... (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

• Dosage ID: ISCA-37034
• ClinGen Curation ID: CCID:006719
• Curation Status: Complete
• Issue Type: Dosage Curation - Gene
• Haploinsufficiency: Gene Associated with Autosomal Recessive Phenotype (30)
• Triplosensitivity: No Evidence for Triplosensitivity (0)
• Last Evaluated: 03/28/2023

Haploinsufficiency (HI) Score Details

• HI Score: 30
• HI Evidence Strength: Gene Associated with Autosomal Recessive Phenotype

HI Disease

• Cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 4

HI Evidence

• PUBMED: 29531481
  Alsahi et al. (2018) reported two homozygous protein-truncating variants in ATP8A2 that were identified in two Saudi families with cerebellar ataxia, intellectual disability, and dysequilibrium syndrome type 4 (CAMRQ4) due to consanguineous marriage. In family #1, a homozygous nonsense variant (c.1741C>T; p.Arg581Ter) was identified in 4 affected siblings. In family #2, a homozygous splice site variant (c.2212-1G>C) was identified in 2 affected sisters. Parents in both families are confirmed heterozygous carriers.
• PUBMED: 35321980
  Narishige et al. (2022) identified two compound heterozygous nonsense variants in ATP8A2 (maternal allele c.1741C>T; p.Arg581Ter in trans with paternal allele c.2158C>T; p.Arg720Ter) by exome-sequencing in two Japanese siblings with cerebellar ataxia, intellectual disability, and dysequilibrium syndrome type 4 (CAMRQ4).
• PUBMED: 31069529
  Ganapathy et al. (2019) reported two homozygous protein-truncating variants in ATP8A2 that were identified in two Indian patients with cerebellar ataxia, intellectual disability, and dysequilibrium syndrome type 4 (CAMRQ4), including a homozygous splice site variant (c.3019-1G>A) in one patient, and a homozygous intragenic deletion involving exons 25-33 in the other patient.
• PUBMED: 35872528
  Dzinovic et al. (2022) identified two frameshift variants in ATP8A2 by exome sequencing in two patients with dystonia and intellectual disability. One patient is homozygous for c.691_701del11 (p.Leu231IlefsTer7); the other patient is compound heterozygous for c.1936_1939delTATC (p.Tyr646ArgfsTer7) and a missense variant c.1874G>A (p.Arg625Gln).
• PUBMED: 30012219
  McMillan et al. (2018) identified biallelic ATP8A2 variants in 11 patients with global developmental delays, severe hypotonia, cognitive impairment, hyperkinetic movement disorders and progressive optic atrophy. Protein-truncating variants reported in this study include a homozygous intragenic deletion involving exons 17-18, a homozygous frameshift (c.3188_3196delCTATGGTCCinsGAAGAAG; p.Thr1063ArgfsTer22), a homozygous nonsense variant (c.1756C>T; p.Arg581Ter), a frameshift (c.1787delA; p.Asn596MetfsTer2) in trans with c.321+3_321+8delAATGGT, and a deletion involving exons 28-33 in trans with c.1185+5G>A resulting in lower expression of ATP8A2 mRNA and protein.

• HI Evidence Comments: The ATP8A2 gene is highly expressed in the brain, spinal cord, retina, and testis and is involved in the transport of aminophospholipids toward the cytoplasmic leaflet in these tissues. Biallelic variants in ATP8A2 are associated with autosomal recessive cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 4. The variant spectrum includes loss-of-function sequence variants and intragenic deletions. Cacciagli et al (2010, PMID: 20683487) reported a de novo balanced translocation t(10;13)(p12.1;q12.13) in a patient with severe intellectual disability and major hypotonia. Break point sequencing identified the disruption on chromosome 13 involving ATP8A2, while no coding regions on chromosome 10 were disrupted. Exon sequencing of ATP8A2 on the other allele did not identify the second variant in trans, suggesting that haploinsufficiency might result in the phenotype. However, at this time, there is insufficient evidence to support haploinsufficiency of ATP8A2 is a disease-causing mechanism.

Triplosensitivity (TS) Score Details

• TS Score: 0
• TS Evidence Strength: No Evidence for Triplosensitivity