GeneBe

NPC2

NPC intracellular cholesterol transporter 2, the group of MD-2 related lipid recognition domain containing|MicroRNA protein coding host genes

Basic information

Region (hg38): 14:74476192-74494177

Links

ENSG00000119655 ∙ NCBI:10577 ∙ OMIM:601015 ∙ HGNC:14537 ∙ Uniprot:P61916 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

  • Niemann-Pick disease, type C2 (Definitive), mode of inheritance: AR
  • Niemann-Pick disease, type C2 (Definitive), mode of inheritance: AR
  • Niemann-Pick disease, type C2 (Strong), mode of inheritance: AR
  • Niemann-Pick disease, type C2 (Strong), mode of inheritance: AR
  • Niemann-Pick disease, type C2 (Strong), mode of inheritance: AR
  • Niemann-Pick disease, type C2 (Definitive), mode of inheritance: AR
  • Niemann-Pick disease type C, severe perinatal form (Supportive), mode of inheritance: AR
  • Niemann-Pick disease type C, severe early infantile neurologic onset (Supportive), mode of inheritance: AR
  • Niemann-Pick disease type C, late infantile neurologic onset (Supportive), mode of inheritance: AR
  • Niemann-Pick disease type C, juvenile neurologic onset (Supportive), mode of inheritance: AR
  • Niemann-Pick disease type C, adult neurologic onset (Supportive), mode of inheritance: AR
  • Niemann-Pick disease, type C2 (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

ConditionInheritanceIntervention CategoriesIntervention/Rationale Manifestation CategoriesReferences
Niemann-pick disease, type C2ARGeneralGenetic 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 describedBiochemical; Gastrointestinal; Neurologic8554047; 11125141; 11567215; 12447927; 17470133; 20301473; 20393800

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the NPC2 gene.

  • Niemann-Pick_disease,_type_C2 (248 variants)
  • not_provided (29 variants)
  • Inborn_genetic_diseases (26 variants)
  • NPC2-related_disorder (13 variants)
  • Niemann-Pick_disease,_type_C1 (8 variants)
  • Niemann-Pick_disease,_type_C (8 variants)
  • not_specified (7 variants)
  • Brain_atrophy (1 variants)
  • Sphingomyelin/cholesterol_lipidosis (1 variants)
  • Global_developmental_delay (1 variants)
  • Seizure (1 variants)
  • Microcephaly (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the NPC2 gene is commonly pathogenic or not. These statistics are base on transcript: NM_000006432.5. Only rare variants are included in the table.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

EffectPLPVUSLBBSum
synonymous
1
clinvar
73
clinvar
 74
missense
2
clinvar
6
clinvar
53
clinvar
1
clinvar
 62
nonsense
9
clinvar
9
clinvar
 18
start loss
4
3
 7
frameshift
9
clinvar
11
clinvar
 20
splice donor/acceptor (+/-2bp)
1
clinvar
6
clinvar
1
clinvar
1
clinvar
 9
Total 25 36 54 75 0

Highest pathogenic variant AF is 0.000120335

Loading clinvar variants...

GnomAD

Source: gnomAD

GeneTypeBio TypeTranscript Coding Exons Length
NPC2protein_codingprotein_codingENST00000555619 517986
pLI Probability
LOF Intolerant 		pRec Probability
LOF Recessive 		Individuals with
no LOFs 		Individuals with
Homozygous LOFs 		Individuals with
Heterozygous LOFs 		Defined p
0.001780.73012478229641257480.00385
Z-Score Observed Expected Observed/Expected Mutation Rate Total Possible in Transcript
Missense1.304779.70.5900.00000388995
Missense in Polyphen1324.3220.5345311
Synonymous-0.9993931.81.230.00000177279
Loss of Function0.84757.500.6663.21e-789

LoF frequencies by population

EthnicitySum of pLOFs p
African & African-American0.002720.00272
Ashkenazi Jewish0.001690.00169
East Asian0.00005440.0000544
Finnish0.002820.00282
European (Non-Finnish)0.006680.00667
Middle Eastern0.00005440.0000544
South Asian0.001440.00144
Other0.003090.00310

dbNSFP

Source: dbNSFP

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.;
Pathway
Lysosome - Homo sapiens (human);Cholesterol metabolism - Homo sapiens (human);TYROBP Causal Network;Ebola Virus Pathway on Host;Ebola Virus Pathway on Host;Neutrophil degranulation;Innate Immune System;Immune System;LDL clearance;Plasma lipoprotein clearance;Transport of small molecules;Plasma lipoprotein assembly, remodeling, and clearance (Consensus)

Recessive Scores

pRec
0.221

Intolerance Scores

loftool
0.422
rvis_EVS
0.28
rvis_percentile_EVS
71.08

Haploinsufficiency Scores

pHI
0.198
hipred
N
hipred_score
0.383
ghis
0.463

Essentials

essential_gene_CRISPR
N
essential_gene_CRISPR2
N
essential_gene_gene_trap
N
gene_indispensability_pred
N
gene_indispensability_score
0.477

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium

Mouse Genome Informatics

Gene name
Npc2
Phenotype
immune system phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); hematopoietic system phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); liver/biliary system phenotype; respiratory system phenotype; cellular phenotype; homeostasis/metabolism phenotype; endocrine/exocrine gland phenotype; growth/size/body region phenotype;

Gene ontology

Biological process
cholesterol metabolic process;response to virus;phospholipid transport;regulation of isoprenoid metabolic process;cholesterol transport;intracellular sterol transport;intracellular cholesterol transport;cholesterol efflux;low-density lipoprotein particle clearance;cholesterol homeostasis;neutrophil degranulation;glycolipid transport
Cellular component
extracellular region;extracellular space;lysosome;endoplasmic reticulum;azurophil granule lumen;lysosomal lumen;extracellular exosome
Molecular function
protein binding;cholesterol binding;cholesterol transporter activity;enzyme binding