NHP2

protein-coding

NHP2 ribonucleoprotein, the group of H/ACA ribonucleoprotein complex

Gene summary

This gene is a member of the H/ACA snoRNPs (small nucleolar ribonucleoproteins) gene family. snoRNPs are involved in various aspects of rRNA processing and modification and have been classified into two families: C/D and H/ACA. The H/ACA snoRNPs also include the DKC1, NOLA1 and NOLA3 proteins. These four H/ACA snoRNP proteins localize to the dense fibrillar components of nucleoli and to coiled (Cajal) bodies in the nucleus. Both 18S rRNA production and rRNA pseudouridylation are impaired if any one of the four proteins is depleted. The four H/ACA snoRNP proteins are also components of the telomerase complex. This gene encodes a protein related to Saccharomyces cerevisiae Nhp2p. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2008]

Previous symbols:

NOLA2

MANE transcript

NM_017838.4

Inheritance

AR, AD

ClinVar variants

P:2U:109B:34

Top phenotype

Dyskeratosis congenita, autosomal recessive 2

gnomAD constraint

pLI —, LoF o/e 0.42

Max pathogenic AF

—

Genomic locus

chr5:178,149,463-178,153,894

External References & Databases

Ensembl (ENSG00000145912)

Transcript & Mutation Effects

hg38 • Region Span ~4.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

dyskeratosis congenita, autosomal recessive 2MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0013519

Submitter: Ambry Genetics

dyskeratosis congenita, autosomal recessive 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013519

Submitter: PanelApp Australia

dyskeratosis congenitaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015780

Submitter: Orphanet

dyskeratosis congenita, autosomal recessive 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013519

Submitter: Labcorp Genetics (formerly Invitae)

dyskeratosis congenita, autosomal recessive 2MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0013519

Submitter: G2P

dyskeratosis congenita, autosomal recessive 2LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0013519

Submitter: ClinGen

NHP2 ribonucleoprotein (*NHP2*) was first reported in relation to autosomal recessive dyskeratosis congenita in 2008 (Vulliamy et al., PMID 18523010). *NHP2* biallelic variant carriers present with features common to other monogenic telomere biology disorders (TBD) like: oral leukoplakia, reticular skin pigmentation, nail dystrophy, bone marrow failure, intellectual disability, and short telomeres. Variation in other telomere related genes like *TERT* and *TERC* have been shown to be related to interstitial lung disease (ILD), but to date ILD has not been observed for this gene-disease entity (PMID 38718684). Seven variants (6 missense, and 1 stop-loss extension) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data from 3 different publications describing a total of 4 probands with ages of onset being reported in both childhood and adulthood. Additionally, 4 families have been reported with heterozygous variant carriers that have presented with features consistent with TBD. The ClinGen Interstitial Lung Disease GCEP has decided to exclude heterozygous cases from this curation due to high population frequencies and/or lack of sufficient detail regarding genotyping. If, however, more convincing data of autosomal dominant inheritance becomes available, the curated entity and classification will be revisited. This gene-disease relationship is supported by protein interaction data, a yeast model and functional alteration in non-patient cells; PMID 11160879, 11074001, 37440454). Experimental data demonstrated that variant NHP2 is related to a decrease in the expression of TERC, and that expression of variant NHP2 and interaction with NOP10 and DKC1 were reduced. The mechanism is unclear but thought to be LOF. In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Interstitial Lung Disease GCEP on the meeting date April 15, 2025(SOP 11). This gene-disease pair was originally evaluated by the General GCEP on June 1, 2017. It was reevaluated on August 1, 2025. Although additional case and experimental evidence (PMIDs: 37440454, 31985013) was published, the classification did not change.

Clinical Genomic Database (CGD)

Dyskeratosis congenita, autosomal recessive 2AR

Manifestation: Allergy/Immunology/Infectious; Dermatologic; Endocrine; Gastrointestinal; Hematologic; Neurologic; Oncologic; Pulmonary

Intervention: Allergy/Immunology/Infectious; Hematologic; Oncologic; Pulmonary

Rationale: Surveillance (eg, with regularly performed CBC as well as other measures in the presence of concern for hematologic sequelae) for bone marrow failure, as well as surveillance for multiple cancer types (eg, with self-examination and clinical examination), and pulmonary disease may allow early detection and treatment; Lung transplant may be indicated in individuals with advanced lung diease; HSCT may be indicated due to manifestations including leukemia and bone marrow failure (which may also be treated with androgen therapy), but the long-term efficacy may not be optimal

Refs: 18523010; 20301779

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NHP2 variants in ClinVar

6 Conditions Cataloged

Dyskeratosis congenitaTotal: 193

not specifiedTotal: 29

not providedTotal: 27

Dyskeratosis congenita, autosomal recessive 2Total: 23

NHP2-related disorderTotal: 7

Dyskeratosis congenita, autosomal recessive 1Total: 5

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_017838.4. 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.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			3 clinvar	31 clinvar		34
missense	2 clinvar		90 clinvar	3 clinvar		95
nonsense			1 clinvar			1
start loss			1 clinvar			1
frameshift			11 clinvar			11
splice donor/acceptor (+/-2bp)			3 clinvar			3
Total	2	0	109	34	0	145

Highest pathogenic variant AF is 6.841405e-7

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 25 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_017838.4	RefSeq	NP_060308.1	4	MANE Select
ENST00000274606.8	Ensembl	ENSP00000274606.4	4	MANE Select
NM_001034833.2	RefSeq	NP_001030005.1	3	Standard
NM_001396110.1	RefSeq	NP_001383039.1	5	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Ribosome biogenesis in eukaryotes - Homo sapiens (human)
rRNA processing
Metabolism of RNA
Telomere Extension By Telomerase
Extension of Telomeres

Biological Process

cleavage involved in rRNA processing
maturation of LSU-rRNA
telomere maintenance via telomerase
rRNA pseudouridine synthesis
snRNA pseudouridine synthesis

Molecular Function

RNA binding
protein binding
box H/ACA snoRNA binding
telomerase RNA binding

Cellular Component

nuclear chromosome, telomeric region
nucleoplasm
telomerase holoenzyme complex
small nucleolar ribonucleoprotein complex
box H/ACA snoRNP complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000274606
Coding exons: 4
Length: 4508
Individuals with no LoFs: 125704
Homozygous LoFs: 0
Heterozygous LoFs: 44
Defined: 125748
p: 0.000175

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.0376	87	88.0	0.989	0.00000419	976
Missense (PolyPhen)		33	30.794	1.0716		379
Synonymous	0.00556	36	36.0	0.999	0.00000171	307
Loss of Function	1.44	3	7.15	0.419	3.92e-7	87

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.00040	0.00040	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000054	0.000054	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00022	0.00022	rare
South Asian	0.000033	0.000033	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Required for ribosome biogenesis and telomere maintenance. Part of the H/ACA small nucleolar ribonucleoprotein (H/ACA snoRNP) complex, which catalyzes pseudouridylation of rRNA. This involves the isomerization of uridine such that the ribose is subsequently attached to C5, instead of the normal N1. Each rRNA can contain up to 100 pseudouridine ("psi") residues, which may serve to stabilize the conformation of rRNAs. May also be required for correct processing or intranuclear trafficking of TERC, the RNA component of the telomerase reverse transcriptase (TERT) holoenzyme. {ECO:0000269|PubMed:15044956}.;
Disease: DISEASE: Dyskeratosis congenita, autosomal recessive, 2 (DKCB2) [MIM:613987]: A rare multisystem disorder caused by defective telomere maintenance. It is characterized by progressive bone marrow failure, and the clinical triad of reticulated skin hyperpigmentation, nail dystrophy, and mucosal leukoplakia. Common but variable features include premature graying, aplastic anemia, low platelets, osteoporosis, pulmonary fibrosis, and liver fibrosis among others. Early mortality is often associated with bone marrow failure, infections, fatal pulmonary complications, or malignancy. {ECO:0000269|PubMed:18523010}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.156

Intolerance Scores

LoFtool: 0.729
RVIS EVS: 0.42
RVIS percentile EVS: 76.81

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.520

Gene Damage Prediction

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