NMNAT2

protein-coding

nicotinamide nucleotide adenylyltransferase 2

Gene summary

This gene product belongs to the nicotinamide mononucleotide adenylyltransferase (NMNAT) enzyme family, members of which catalyze an essential step in NAD (NADP) biosynthetic pathway. Unlike the other human family member, which is localized to the nucleus, and is ubiquitously expressed; this enzyme is cytoplasmic, and is predominantly expressed in the brain. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

Previous symbols:

C1orf15

MANE transcript

NM_015039.4

Inheritance

ClinVar variants

P:2U:29

Top phenotype

Junctional epidermolysis bullosa, non-Herlitz type

gnomAD constraint

pLI —, LoF o/e 0.06

Max pathogenic AF

—

Genomic locus

chr1:183,248,237-183,418,380

External References & Databases

Ensembl (ENSG00000157064)

Transcript & Mutation Effects

hg38 • Region Span ~170.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

peripheral vascular diseaseMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0005294

Submitter: PanelApp Australia

developmental defect during embryogenesisMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0019755

Submitter: PanelApp Australia

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NMNAT2 variants in ClinVar

5 Conditions Cataloged

not specifiedTotal: 25

Junctional epidermolysis bullosa, non-Herlitz typeTotal: 2

not providedTotal: 1

Inborn genetic diseasesTotal: 1

Vascular dementiaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_015039.4. 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						0
missense		1 clinvar	27 clinvar			28
nonsense			1 clinvar			1
start loss						0
frameshift		1 clinvar	1 clinvar			2
splice donor/acceptor (+/-2bp)						0
Total	0	2	29	0	0	31

Highest pathogenic variant AF is 0.00001369576

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 11 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_015039.4	RefSeq	NP_055854.1	11	MANE Select
ENST00000287713.7	Ensembl	ENSP00000287713.6	11	MANE Select
NM_170706.4	RefSeq	NP_733820.1	11	Standard
ENST00000294868.8	Ensembl	ENSP00000294868.4	11	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Nicotinate and nicotinamide metabolism - Homo sapiens (human)
Nicotinate and Nicotinamide Metabolism
NAD+ metabolism
Metabolism
Nicotinate Nicotinamide metabolism

Biological Process

NAD biosynthetic process
NAD metabolic process
'de novo' NAD biosynthetic process from aspartate

Molecular Function

nicotinamide-nucleotide adenylyltransferase activity
nicotinate-nucleotide adenylyltransferase activity
ATP binding

Cellular Component

Golgi membrane
late endosome
Golgi apparatus
trans-Golgi network
axon

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000287713
Coding exons: 11
Length: 170366
Individuals with no LoFs: 125741
Homozygous LoFs: 0
Heterozygous LoFs: 2
Defined: 125743
p: 0.00000795

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.10	110	192	0.573	0.0000114	2022
Missense (PolyPhen)		40	76.742	0.52123		761
Synonymous	0.0524	75	75.6	0.992	0.00000481	589
Loss of Function	3.70	1	17.9	0.0559	8.44e-7	201

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.0000088	0.0000088	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Nicotinamide/nicotinate-nucleotide adenylyltransferase that acts as an axon maintenance factor (By similarity). Catalyzes the formation of NAD(+) from nicotinamide mononucleotide (NMN) and ATP (PubMed:16118205, PubMed:17402747). Can also use the deamidated form; nicotinic acid mononucleotide (NaMN) as substrate but with a lower efficiency (PubMed:16118205, PubMed:17402747). Cannot use triazofurin monophosphate (TrMP) as substrate (PubMed:16118205, PubMed:17402747). Also catalyzes the reverse reaction, i.e. the pyrophosphorolytic cleavage of NAD(+) (PubMed:16118205, PubMed:17402747). For the pyrophosphorolytic activity prefers NAD(+), NADH and NaAD as substrates and degrades nicotinic acid adenine dinucleotide phosphate (NHD) less effectively (PubMed:16118205, PubMed:17402747). Fails to cleave phosphorylated dinucleotides NADP(+), NADPH and NaADP(+) (PubMed:16118205, PubMed:17402747). Axon survival factor required for the maintenance of healthy axons: acts by delaying Wallerian axon degeneration, an evolutionarily conserved process that drives the loss of damaged axons (By similarity). {ECO:0000250|UniProtKB:Q8BNJ3, ECO:0000269|PubMed:16118205, ECO:0000269|PubMed:17402747}.;

Recessive Scores

pRec: 0.134

Intolerance Scores

LoFtool: 0.0269
RVIS EVS: -0.03
RVIS percentile EVS: 51.4

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.831

Gene Damage Prediction

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