NT5C2

protein-coding

5'-nucleotidase, cytosolic II, the group of 5'-nucleotidases

Gene summary

This gene encodes a hydrolase that serves as an important role in cellular purine metabolism by acting primarily on inosine 5'-monophosphate and other purine nucleotides. [provided by RefSeq, Oct 2011]

Previous symbols:

NT5B
SPG45

MANE transcript

NM_001351169.2

Inheritance

ClinVar variants

P:31U:85B:58

Top phenotype

Spastic paraplegia 45, autosomal recessive

gnomAD constraint

pLI —, LoF o/e 0.46

Max pathogenic AF

—

Genomic locus

chr10:103,087,185-103,277,605

External References & Databases

Ensembl (ENSG00000076685)

Transcript & Mutation Effects

hg38 • Region Span ~190.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hereditary spastic paraplegia 45SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013165

Submitter: Orphanet

hereditary spastic paraplegia 45MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0013165

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.

complex hereditary spastic paraplegiaDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0015150

Submitter: ClinGen

*NT5C2* was first reported in relation to autosomal recessive complex hereditary spastic paraplegia in 2014 (Novarino *et al.*, PMID: 24482476). Autosomal recessive spastic paraplegia 45 (SPG45) with intellectual disability was originally mapped to 10q24.3-q25.1 in a large consanguineous Turkish family in 2009 (Dursun *et al.*, PMID: 19415352). Novarino *et al.* later studied the same family and identified the causative homozygous truncating variant in *NT5C2* by exome sequencing, as well as identifying four additional families with homozygous loss-of-function mutations in *NT5C2*. *NT5C2* encodes the 5'-Nucleotidase Cytosolic II protein which regulates intracellular purine/pyrimidine nucleotides in cooperation with other nucleotidases. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, a single disease assertion exists for NT5C2 and we found no difference in molecular mechanism or inheritance pattern. 7 variants (1 missense, 1 in-frame deletion, 1 nonsense, 4 splice variants) that have been reported in 7 probands in 5 publications (PMIDs: 28884889, 32153630, 28327087, 29123918, 24482476) are included in this curation. More evidence, including additional genetic data and segregation data, is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is reported to be loss of function. In summary, there is definitive evidence supporting the relationship between *NT5C2* and autosomal recessive complex hereditary spastic paraplegia. 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 Cerebral Palsy GCEP on the meeting date September 5th 2024 (SOP Version 10).

hereditary spastic paraplegia 45STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013165

Submitter: PanelApp Australia

hereditary spastic paraplegia 45STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013165

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Spastic paraplegia 45, autosomal recessiveAR

Manifestation: Neurologic; Ophthalmologic

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

Refs: 19415352; 24482476

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NT5C2 variants in ClinVar

8 Conditions Cataloged

Hereditary spastic paraplegia 45Total: 190

not providedTotal: 65

Inborn genetic diseasesTotal: 40

not specifiedTotal: 25

NT5C2-related disorderTotal: 9

Hereditary spastic paraplegiaTotal: 8

Neurodevelopmental disorderTotal: 1

MicrocephalyTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001351169.2. 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			1 clinvar	56 clinvar		57
missense	1 clinvar	2 clinvar	75 clinvar	2 clinvar		80
nonsense	6 clinvar	2 clinvar				8
start loss						0
frameshift	6 clinvar	4 clinvar				10
splice donor/acceptor (+/-2bp)	4 clinvar	6 clinvar	9 clinvar			19
Total	17	14	85	58	0	174

Highest pathogenic variant AF is 0.000040899642

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 188 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001351169.2	RefSeq	NP_001338098.1	17	MANE Select
ENST00000404739.8	Ensembl	ENSP00000383960.3	17	MANE Select
NM_001134373.3	RefSeq	NP_001127845.1	17	Standard
NM_001351170.2	RefSeq	NP_001338099.1	18	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Pyrimidine metabolism - Homo sapiens (human)
Nicotinate and nicotinamide metabolism - Homo sapiens (human)
Purine metabolism - Homo sapiens (human)
Purine Nucleoside Phosphorylase Deficiency
Mercaptopurine Action Pathway

Biological Process

purine nucleotide catabolic process
phosphorylation
dephosphorylation
drug metabolic process
IMP metabolic process

Molecular Function

nucleotide binding
protein binding
5'-nucleotidase activity
metal ion binding
nucleoside phosphotransferase activity

Cellular Component

cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000343289
Coding exons: 17
Length: 107117
Individuals with no LoFs: 125688
Homozygous LoFs: 0
Heterozygous LoFs: 58
Defined: 125746
p: 0.000231

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.64	181	312	0.579	0.0000170	3714
Missense (PolyPhen)		35	80.908	0.43259		1032
Synonymous	-0.761	117	107	1.09	0.00000513	1017
Loss of Function	2.88	15	32.8	0.458	0.00000169	408

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.00012	0.00012	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.00016	0.00016	rare
Finnish	0.0011	0.0011	notable
European (Non-Finnish)	0.00020	0.00020	rare
South Asian	0.000065	0.000065	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: May have a critical role in the maintenance of a constant composition of intracellular purine/pyrimidine nucleotides in cooperation with other nucleotidases. Preferentially hydrolyzes inosine 5'-monophosphate (IMP) and other purine nucleotides.;
Disease: DISEASE: Spastic paraplegia 45, autosomal recessive (SPG45) [MIM:613162]: A form of spastic paraplegia, a neurodegenerative disorder characterized by a slow, gradual, progressive weakness and spasticity of the lower limbs. Rate of progression and the severity of symptoms are quite variable. Initial symptoms may include difficulty with balance, weakness and stiffness in the legs, muscle spasms, and dragging the toes when walking. In some forms of the disorder, bladder symptoms (such as incontinence) may appear, or the weakness and stiffness may spread to other parts of the body. Some SPG45 patients manifest mental retardation, contractures and learning disability. {ECO:0000269|PubMed:24482476, ECO:0000269|PubMed:28884889}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.281

Intolerance Scores

LoFtool: 0.657
RVIS EVS: -0.2
RVIS percentile EVS: 38.82

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Indispensability pred.: N
Indispensability score: 0.338

Gene Damage Prediction

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