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): 14:74476191-74494177

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 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
• Niemann-Pick disease, type C2 (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Niemann-pick disease, type C2	AR	General	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	Biochemical; Gastrointestinal; Neurologic	8554047; 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 (187 variants)
• not provided (35 variants)
• Inborn genetic diseases (17 variants)
• Niemann-Pick disease, type C1 (14 variants)
• Niemann-Pick disease, type C (8 variants)
• not specified (7 variants)
• NPC2-related condition (2 variants)
• Global developmental delay;Brain atrophy;Seizure;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.

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.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			3	51		54
missense	2	2	40	4		48
nonsense	6	10	1			17
start loss	2	4				6
frameshift	5	9	1			15
inframe indel			1			1
splice donor/acceptor (+/-2bp)		4				4
splice region			4	8	1	13
non coding			6	34	4	44
Total	15	29	52	89	4

Highest pathogenic variant AF is 0.0000723

Variants in NPC2

This is a list of pathogenic ClinVar variants found in the NPC2 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
14-74479979-G-C		Niemann-Pick disease, type C1	Conflicting classifications of pathogenicity (Jun 01, 2023)
14-74480003-G-A		Niemann-Pick disease, type C1	Benign/Likely benign (Jul 15, 2018)
14-74480021-TA-T			Likely benign (Jul 05, 2018)
14-74480037-C-T		Niemann-Pick disease, type C1	Uncertain significance (Jan 13, 2018)
14-74480120-C-T			Likely benign (Mar 18, 2021)
14-74480159-G-A		Niemann-Pick disease, type C1	Uncertain significance (Jan 12, 2018)
14-74480188-C-T		Niemann-Pick disease, type C1	Uncertain significance (Jan 12, 2018)
14-74480265-A-G		not specified • Niemann-Pick disease, type C1	Benign/Likely benign (May 09, 2020)
14-74480272-A-C			Uncertain significance (Jan 27, 2017)
14-74480275-T-C		Niemann-Pick disease, type C2	Likely benign (Sep 13, 2023)
14-74480276-A-G		Niemann-Pick disease, type C2	Uncertain significance (Apr 18, 2020)
14-74480277-G-A		Niemann-Pick disease, type C2	Likely benign (Oct 25, 2021)
14-74480277-G-C		Niemann-Pick disease, type C2	Conflicting classifications of pathogenicity (Jul 07, 2023)
14-74480280-A-G		Niemann-Pick disease, type C2 • Inborn genetic diseases • NPC2-related disorder	Conflicting classifications of pathogenicity (Jan 22, 2024)
14-74480289-C-T		Niemann-Pick disease, type C2	Uncertain significance (Jan 05, 2018)
14-74480292-T-C		Niemann-Pick disease, type C2	Likely benign (Aug 17, 2023)
14-74480292-T-G		not specified • Niemann-Pick disease, type C1 • Niemann-Pick disease, type C2	Benign/Likely benign (Feb 01, 2024)
14-74480296-T-C		Niemann-Pick disease, type C2	Likely benign (Mar 12, 2023)
14-74480296-T-G		Niemann-Pick disease, type C2	Likely benign (Jan 25, 2024)
14-74480297-G-A		Niemann-Pick disease, type C2	Likely benign (Nov 02, 2023)
14-74480298-T-C		Niemann-Pick disease, type C2	Likely benign (Jul 02, 2022)
14-74480301-T-C		Niemann-Pick disease, type C2	Likely benign (Dec 14, 2023)
14-74480305-C-G		Niemann-Pick disease, type C2	Likely benign (Dec 26, 2023)
14-74480305-C-T		Niemann-Pick disease, type C2	Likely benign (Jul 30, 2023)
14-74480389-C-A			Likely benign (Jul 14, 2018)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
NPC2	protein_coding	protein_coding	ENST00000555619	5	17986

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.00178	0.730	124782	2	964	125748	0.00385

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.30	47	79.7	0.590	0.00000388	995
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00272	0.00272
Ashkenazi Jewish	0.00169	0.00169
East Asian	0.0000544	0.0000544
Finnish	0.00282	0.00282
European (Non-Finnish)	0.00668	0.00667
Middle Eastern	0.0000544	0.0000544
South Asian	0.00144	0.00144
Other	0.00309	0.00310

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

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

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