GeneBe

ATP7B

protein-coding

ATPase copper transporting beta, the group of ATPase copper transporting

Gene summary

This gene is a member of the P-type cation transport ATPase family and encodes a protein with several membrane-spanning domains, an ATPase consensus sequence, a hinge domain, a phosphorylation site, and at least 2 putative copper-binding sites. This protein is a monomer, and functions as a copper-transporting ATPase which exports copper out of the cells, such as the efflux of hepatic copper into the bile. Alternate transcriptional splice variants, encoding different isoforms with distinct cellular localizations, have been characterized. Mutations in this gene have been associated with Wilson disease which is characterized by copper accumulation. [provided by RefSeq, Dec 2019]

Previous symbols:
  • WND

MANE transcript

NM_000053.4

Inheritance

AR

ClinVar variants

P:991U:1150B:908

Top phenotype

Wilson disease

gnomAD constraint

pLI —, LoF o/e 0.93

Max pathogenic AF

—

Genomic locus

chr13:51,930,436-52,012,125

External References & Databases

Ensembl (ENSG00000123191)NCBI Gene (540)OMIM (606882)HGNC:870GenCCUniProt (P35670)AlphaFoldClinVar (ATP7B)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~81.7 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Wilson diseaseSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010200

Submitter: Genomics England PanelApp

Wilson diseaseDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010200

Submitter: ClinGen

The relationship between ATP7B and Wilson disease (autosomal recessive) was evaluated using the ClinGen Clinical Validity Framework as of March 26th, 2019. Variants in ATP7B were first reported in humans with this disease as early as 1993 (Bull et al., PMID 8298639). Wilson disease is a disorder of copper metabolism characterized by an accumulation of copper in many organs, particularly the liver and brain. At least 700 unique germline variants have been identified (missense, nonsense, splice site, frameshift) (reviewed in Członkowska et al., 2018; PMID 30190489). This gene-disease relationship is well-known and therefore a significant amount of case-level data, segregation data and experimental data is available in the literature, therefore the maximum score for both genetic evidence and experimental evidence has been reached. Note, this curation effort may not be exhaustive of all literature related to this gene-disease relationship. The mutational mechanism for disease is loss of function leading to reduced (or absent) copper-transporter activity (Huster et al., 2012; PMID 22240481). This gene-disease association is supported by expression studies, in vitro functional assays, and animal models. In summary, ATP7B is definitively associated with autosomal recessive Wilson disease. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen General Gene Curation Expert Panel on March 27, 2019.

Wilson diseaseSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010200

Submitter: Orphanet

Wilson diseaseDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010200

Submitter: Natera

Wilson diseaseSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010200

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Wilson diseaseAR

Manifestation: Biochemical; Gastrointestinal; Neurologic; Ophthalmologic

Intervention: Biochemical; Gastrointestinal

Rationale: Dietary measures (eg, avoidance of copper-containing foods), as well as medications (eg, penicillamine, zinc, vitamin B6, tetrathiomolybdate), and possible liver transplant, can be beneficial

Refs: 463930; 3900322; 3561699; 3328213; 8298639; 8298641; 8201263; 7884606; 8610495; 9794697; 10435491; 10435489; 10673307; 12376745; 12633149; 12756138; 16283883; 16216950; 20301685; 16606763; 21901655; 22327203; 21832955; 22083169Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ATP7B variants in ClinVar

16 Conditions Cataloged
Wilson diseaseTotal: 3283
not providedTotal: 596
not specifiedTotal: 278
Inborn genetic diseasesTotal: 246
ATP7B-related disorderTotal: 82
Epileptic encephalopathyTotal: 2
See casesTotal: 2
Hand tremorTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000053.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

EffectPLPVUSLBBSum
synonymous
2
clinvar
5
clinvar
33
clinvar
831
clinvar
20
clinvar
 891
missense
54
clinvar
304
clinvar
1106
clinvar
48
clinvar
8
clinvar
 1520
nonsense
64
clinvar
69
clinvar
3
clinvar
 136
start loss
1
clinvar
 1
frameshift
182
clinvar
207
clinvar
5
clinvar
1
clinvar
 395
splice donor/acceptor (+/-2bp)
26
clinvar
77
clinvar
3
clinvar
 106
Total3286631150879293049

Highest pathogenic variant AF is 0.0032157986

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 74 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_000053.4RefSeqNP_000044.221MANE Select
ENST00000242839.10EnsemblENSP00000242839.521MANE Select
NM_001005918.3RefSeqNP_001005918.117Standard
NM_001243182.2RefSeqNP_001230111.122Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Platinum Pathway, Pharmacokinetics/Pharmacodynamics
  • Copper homeostasis
  • Ion channel transport
  • Transport of small molecules
  • Ion transport by P-type ATPases

Biological Process

  • copper ion transport
  • cellular copper ion homeostasis
  • cellular zinc ion homeostasis
  • lactation
  • copper ion import

Molecular Function

  • copper-exporting ATPase activity
  • copper ion transmembrane transporter activity
  • copper ion binding
  • protein binding
  • ATP binding

Cellular Component

  • Golgi membrane
  • mitochondrion
  • late endosome
  • Golgi apparatus
  • trans-Golgi network

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000242839
Coding exons
21
Length
78822
Individuals with no LoFs
124554
Homozygous LoFs
0
Heterozygous LoFs
294
Defined
124848
p
0.00118
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense-0.8818858141.090.00004719571
Missense (PolyPhen)359355.111.01094109
Synonymous-1.023573331.070.00002223041
Loss of Function0.4484750.40.9320.00000231651

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000450.00045rare
Latino/Admixed American0.000550.00055rare
Ashkenazi Jewish0.000600.00060rare
East Asian0.00120.0012notable
Finnish0.000740.00074rare
European (Non-Finnish)0.00150.0015notable
South Asian0.00160.0016notable
Other0.00120.0012notable

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Copper ion transmembrane transporter involved in the export of copper out of the cells. It is involved in copper homeostasis in the liver, where it ensures the efflux of copper from hepatocytes into the bile in response to copper overload. {ECO:0000269|PubMed:18203200, ECO:0000269|PubMed:22240481, ECO:0000269|PubMed:24706876, ECO:0000269|PubMed:26004889}.;
Disease
DISEASE: Wilson disease (WD) [MIM:277900]: An autosomal recessive disorder of copper metabolism in which copper cannot be incorporated into ceruloplasmin in liver, and cannot be excreted from the liver into the bile. Copper accumulates in the liver and subsequently in the brain and kidney. The disease is characterized by neurologic manifestations and signs of cirrhosis. {ECO:0000269|PubMed:10051024, ECO:0000269|PubMed:10194254, ECO:0000269|PubMed:10447265, ECO:0000269|PubMed:10453196, ECO:0000269|PubMed:10502776, ECO:0000269|PubMed:10502777, ECO:0000269|PubMed:10544227, ECO:0000269|PubMed:10721669, ECO:0000269|PubMed:10790207, ECO:0000269|PubMed:10942420, ECO:0000269|PubMed:11043508, ECO:0000269|PubMed:11093740, ECO:0000269|PubMed:11180609, ECO:0000269|PubMed:11216666, ECO:0000269|PubMed:11231950, ECO:0000269|PubMed:11243728, ECO:0000269|PubMed:11405812, ECO:0000269|PubMed:11690702, ECO:0000269|PubMed:11954751, ECO:0000269|PubMed:12325021, ECO:0000269|PubMed:12376745, ECO:0000269|PubMed:12544487, ECO:0000269|PubMed:14639035, ECO:0000269|PubMed:14966923, ECO:0000269|PubMed:14986826, ECO:0000269|PubMed:15024742, ECO:0000269|PubMed:15557537, ECO:0000269|PubMed:15811015, ECO:0000269|PubMed:15845031, ECO:0000269|PubMed:15952988, ECO:0000269|PubMed:15967699, ECO:0000269|PubMed:16088907, ECO:0000269|PubMed:16207219, ECO:0000269|PubMed:16283883, ECO:0000269|PubMed:16649058, ECO:0000269|PubMed:17718866, ECO:0000269|PubMed:17823867, ECO:0000269|PubMed:17919502, ECO:0000269|PubMed:17949296, ECO:0000269|PubMed:18203200, ECO:0000269|PubMed:18373411, ECO:0000269|PubMed:19033537, ECO:0000269|PubMed:20333758, ECO:0000269|PubMed:21398519, ECO:0000269|PubMed:21454443, ECO:0000269|PubMed:21645214, ECO:0000269|PubMed:21682854, ECO:0000269|PubMed:22075048, ECO:0000269|PubMed:22240481, ECO:0000269|PubMed:22484412, ECO:0000269|PubMed:22763723, ECO:0000269|PubMed:23159873, ECO:0000269|PubMed:23235335, ECO:0000269|PubMed:23275100, ECO:0000269|PubMed:23333878, ECO:0000269|PubMed:23518715, ECO:0000269|PubMed:23962630, ECO:0000269|PubMed:24476933, ECO:0000269|PubMed:24555712, ECO:0000269|PubMed:24706876, ECO:0000269|PubMed:25704634, ECO:0000269|PubMed:25982861, ECO:0000269|PubMed:26004889, ECO:0000269|PubMed:28856630, ECO:0000269|PubMed:7626145, ECO:0000269|PubMed:8298641, ECO:0000269|PubMed:8533760, ECO:0000269|PubMed:8782057, ECO:0000269|PubMed:8931691, ECO:0000269|PubMed:8938442, ECO:0000269|PubMed:8980283, ECO:0000269|PubMed:9222767, ECO:0000269|PubMed:9311736, ECO:0000269|PubMed:9452121, ECO:0000269|PubMed:9482578, ECO:0000269|PubMed:9554743, ECO:0000269|PubMed:9671269, ECO:0000269|PubMed:9772425, ECO:0000269|PubMed:9829905, ECO:0000269|PubMed:9837819, ECO:0000269|PubMed:9887381}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.636

Intolerance Scores

LoFtool
0.0340
RVIS EVS
-0.34
RVIS percentile EVS
30.38

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.805

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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