NPC2
protein-codingNPC intracellular cholesterol transporter 2, the group of MD-2 related lipid recognition domain containing|MicroRNA protein coding host genes
Gene summary
This gene encodes a protein containing a lipid recognition domain. The encoded protein may function in regulating the transport of cholesterol through the late endosomal/lysosomal system. Mutations in this gene have been associated with Niemann-Pick disease, type C2 and frontal lobe atrophy. [provided by RefSeq, Jul 2008]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~18.0 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0016306
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0016309
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0016307
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0011873
Submitter: ClinGen
The relationship between NPC2 and Niemann-Pick disease, type C2, an autosomal recessive lysosomal storage disorder, was evaluated using the ClinGen Clinical Validity Framework as of April 4, 2022. Niemann-Pick disease, type C (NPC) is characterized by abnormal intracellular accumulation of cholesterol (which can be detected by filipin staining or, more recently, by measurement of oxysterols) and glycosphingolipids in various tissues. The clinical presentation typically depends upon age of onset and includes visceral features, such as hepatosplenomegaly, jaundice, and pulmonary infiltrates (in some cases) in infancy, and neurological features including hypotonia and developmental delay in late infancy, with later development of ataxia, dysarthria, dysphagia, seizures, dystonia, gelastic cataplexy, and cognitive impairment. Older teenagers and young adults may present with early-onset dementia or psychiatric manifestations (Patterson, 2020, PMID: 20301473). About 95% of cases of NPC are caused by biallelic variants in NPC1 and 5% by variants in NPC2; symptoms in individuals with variants in these genes are indistinguishable (Patterson, 2020, PMID: 20301473). NPC2 encodes a soluble lysosomal protein with cholesterol binding properties (Xu et al, PMID: 31843136). Biallelic variants in NPC2 were first reported in patients with Niemann-Pick disease, type C2, by Naureckiene et al in 2000 (PMID: 11125141). Since then, over 20 variants have been reported in about 50 cases worldwide (Xu et al, 2019, PMID: 31843136). The disease mechanism is loss of function. In this curation, data on 8 unique variants (missense, nonsense, splice site) from 8 probands from 3 publications were collected (Millat et al, 2001, PMID: 11567215; Chikk et al, 2005, PMID: 15937921; Verot et al, 2007, PMID: 17470133). This includes c.58G>T (p.Glu20Ter), which is reported to account for >50% of Niemann Pick type C2 alleles (Millat et al, 2001, PMID: 11567215). Further information is available in the literature but the maximum score for genetic evidence (12 points) has been reached. Experimental evidence supporting this gene-disease relationship includes the biochemical function of NPC2, which is consistent with the biochemical and clinical findings in patients (Xu et al, PMID: 31843136); interaction of NPC2 with NPC1, another gene involved in Niemann-Pick disease, type C (Deffieu and Pfeffer, 2011, PMID: 22065762); functional alteration studies demonstrating the importance of glycosylation of Asn58 in the localization and function of NPC2 (Chikh et al, 2004, PMID: 15542393); the biochemical, clinical features, and histological features of an NPC2 hypomorphic mouse (Sleat et al, 2004, PMID: 15071184); rescue of abnormal cholesterol accumulation in NPC2 fibroblasts by medium conditioned by NPC2-expressing cells (Naureckiene et al, 2000, PMID: 11125141); and rescue of phenotypic features and visceral cholesterol accumulation in NPC-/- mice by treatment with bivine NPC protein (Nielsen et al 22073306). Additional experimental evidence is available in the literature but the maximum points for experimental evidence (6 points) has been reached. In summary, NPC2 is definitively associated with Niemann-Pick disease, type C2. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This clinical validity classification was approved by the Lysosomal Diseases GCEP on April 5th, 2022 (SOP version #8).
Inheritance Pattern: AR
Disease ID:MONDO:0016310
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0016308
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0011873
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0011873
Submitter: Genomics England PanelApp
Inheritance Pattern: AR
Disease ID:MONDO:0011873
Submitter: Laboratory for Molecular Medicine
This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.
Inheritance Pattern: AR
Disease ID:MONDO:0011873
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0011873
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0011873
Submitter: Natera
Inheritance Pattern: AR
Disease ID:MONDO:0011873
Submitter: Myriad Women's Health
Clinical Genomic Database (CGD)
Manifestation: Biochemical; Gastrointestinal; Neurologic
Intervention: General
Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing; BMT has been described
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to NPC2 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_006432.5. 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.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 77 | 77 | ||||
| missense | 2 | 4 | 59 | 1 | 66 | |
| nonsense | 9 | 9 | 18 | |||
| start loss | 4 | 3 | 7 | |||
| frameshift | 13 | 12 | 25 | |||
| splice donor/acceptor (+/-2bp) | 1 | 6 | 4 | 1 | 12 | |
| Total | 29 | 34 | 63 | 79 | 0 | 205 |
Highest pathogenic variant AF is 0.0001203353
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_006423.1 | 5 | MANE Select | |
| Ensembl | ENSP00000451112.2 | 5 | MANE Select | |
| RefSeq | NP_001350617.1 | 4 | Standard | |
| RefSeq | NP_001362369.1 | 4 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Lysosome - Homo sapiens (human)
- Cholesterol metabolism - Homo sapiens (human)
- TYROBP Causal Network
- Ebola Virus Pathway on Host
- Ebola Virus Pathway on Host
Biological Process
- cholesterol metabolic process
- response to virus
- phospholipid transport
- regulation of isoprenoid metabolic process
- cholesterol transport
Molecular Function
- protein binding
- cholesterol binding
- cholesterol transporter activity
- enzyme binding
Cellular Component
- extracellular region
- extracellular space
- lysosome
- endoplasmic reticulum
- azurophil granule lumen
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000555619
- Coding exons
- 5
- Length
- 17986
- Individuals with no LoFs
- 124782
- Homozygous LoFs
- 2
- Heterozygous LoFs
- 964
- Defined
- 125748
- p
- 0.00385
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.30 | 47 | 79.7 | 0.590 | 0.00000388 | 995 |
| Missense (PolyPhen) | 13 | 24.322 | 0.5345 | 311 | ||
| Synonymous | -0.999 | 39 | 31.8 | 1.23 | 0.00000177 | 279 |
| Loss of Function | 0.847 | 5 | 7.50 | 0.666 | 3.21e-7 | 89 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.0014 | 0.0014 | notable |
| Latino/Admixed American | 0.0013 | 0.0013 | notable |
| Ashkenazi Jewish | 0.0017 | 0.0017 | notable |
| East Asian | 0.000054 | 0.000054 | rare |
| Finnish | 0.0028 | 0.0028 | notable |
| European (Non-Finnish) | 0.0067 | 0.0067 | notable |
| South Asian | 0.0014 | 0.0014 | notable |
| Other | 0.0031 | 0.0031 | notable |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Intracellular cholesterol transporter which acts in concert with NPC1 and plays an important role in the egress of cholesterol from the lysosomal compartment (PubMed:17018531, PubMed:11125141, PubMed:18772377, PubMed:29580834, PubMed:15937921). Unesterified cholesterol that has been released from LDLs in the lumen of the late endosomes/lysosomes is transferred by NPC2 to the cholesterol-binding pocket in the N- terminal domain of NPC1 (PubMed:17018531, PubMed:18772377, PubMed:27238017). May bind and mobilize cholesterol that is associated with membranes (PubMed:18823126). NPC2 binds cholesterol with a 1:1 stoichiometry (PubMed:17018531). Can bind a variety of sterols, including lathosterol, desmosterol and the plant sterols stigmasterol and beta-sitosterol (PubMed:17018531). The secreted form of NCP2 regulates biliary cholesterol secretion via stimulation of ABCG5/ABCG8-mediated cholesterol transport (By similarity). {ECO:0000250|UniProtKB:Q9Z0J0, ECO:0000269|PubMed:11125141, ECO:0000269|PubMed:15937921, ECO:0000269|PubMed:17018531, ECO:0000269|PubMed:18772377, ECO:0000269|PubMed:18823126, ECO:0000269|PubMed:27238017, ECO:0000269|PubMed:29580834}.;
- Disease
- DISEASE: Niemann-Pick disease C2 (NPC2) [MIM:607625]: A lysosomal storage disorder that affects the viscera and the central nervous system. It is due to defective intracellular processing and transport of low-density lipoprotein derived cholesterol. It causes accumulation of cholesterol in lysosomes, with delayed induction of cholesterol homeostatic reactions. Niemann-Pick disease type C2 has a highly variable clinical phenotype. Clinical features include variable hepatosplenomegaly and severe progressive neurological dysfunction such as ataxia, dystonia and dementia. The age of onset can vary from infancy to late adulthood. {ECO:0000269|PubMed:11125141, ECO:0000269|PubMed:11567215, ECO:0000269|PubMed:12447927, ECO:0000269|PubMed:12955717, ECO:0000269|PubMed:15937921, ECO:0000269|PubMed:16126423, ECO:0000269|PubMed:18772377}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.221
Intolerance Scores
- LoFtool
- 0.422
- RVIS EVS
- 0.28
- RVIS percentile EVS
- 71.08
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.477
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |