GeneBe

NPR2

protein-coding

natriuretic peptide receptor 2, the group of Transmembrane guanylate cyclases|DENN domain containing

Gene summary

This gene encodes natriuretic peptide receptor B, one of two integral membrane receptors for natriuretic peptides. Both NPR1 and NPR2 contain five functional domains: an extracellular ligand-binding domain, a single membrane-spanning region, and intracellularly a protein kinase homology domain, a helical hinge region involved in oligomerization, and a carboxyl-terminal guanylyl cyclase catalytic domain. The protein is the primary receptor for C-type natriuretic peptide (CNP), which upon ligand binding exhibits greatly increased guanylyl cyclase activity. Mutations in this gene are the cause of acromesomelic dysplasia Maroteaux type. [provided by RefSeq, Jul 2008]

Previous symbols:
  • ANPRB
  • NPRB
  • AMDM

MANE transcript

NM_003995.4

Inheritance

AR, AD

ClinVar variants

P:116U:409B:134

Top phenotype

Epiphyseal chondrodysplasia, Miura type; Short stature with nonspecific skeletal abnormalities 1; Acromesomelic dysplasia 1

gnomAD constraint

pLI —, LoF o/e 0.33

Max pathogenic AF

—

Genomic locus

chr9:35,791,003-35,809,732

External References & Databases

Ensembl (ENSG00000159899)NCBI Gene (4882)OMIM (108961)HGNC:7944GenCCUniProt (P20594)AlphaFoldClinVar (NPR2)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~18.7 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

acromesomelic dysplasia 1, Maroteaux typeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011275

Submitter: Orphanet

tall stature-scoliosis-macrodactyly of the great toes syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014401

Submitter: Orphanet

acromesomelic dysplasia 1, Maroteaux typeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011275

Submitter: PanelApp Australia

short stature with nonspecific skeletal abnormalities 1MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0014551

Submitter: Ambry Genetics

tall stature-scoliosis-macrodactyly of the great toes syndromeMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0014401

Submitter: Ambry Genetics

acromesomelic dysplasia 1, Maroteaux typeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011275

Submitter: Ambry Genetics

acromesomelic dysplasia 1, Maroteaux typeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011275

Submitter: Labcorp Genetics (formerly Invitae)

tall stature-scoliosis-macrodactyly of the great toes syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014401

Submitter: Labcorp Genetics (formerly Invitae)

acromesomelic dysplasia 1, Maroteaux typeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011275

Submitter: G2P

bone disorderSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0005381

Submitter: PanelApp Australia

short stature with nonspecific skeletal abnormalities 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014551

Submitter: Labcorp Genetics (formerly Invitae)

tall stature-scoliosis-macrodactyly of the great toes syndromeMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0014401

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Epiphyseal chondrodysplasia, Miura type; Short stature with nonspecific skeletal abnormalities 1; Acromesomelic dysplasia 1AD/AR

Manifestation: Musculoskeletal

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: 15146390; 16384845; 22691581; 22870295; 24001744; 24057292; 24259409; 24471569; 26336901; 26537434Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NPR2 variants in ClinVar

19 Conditions Cataloged
Acromesomelic dysplasia 1, Maroteaux typeTotal: 574
Tall stature-scoliosis-macrodactyly of the great toes syndromeTotal: 526
not providedTotal: 120
Inborn genetic diseasesTotal: 96
not specifiedTotal: 64
NPR2-related disorderTotal: 34
Short stature with nonspecific skeletal abnormalitiesTotal: 28
Short stature with nonspecific skeletal abnormalities 1Total: 16

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_003995.4. 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.

EffectPLPVUSLBBSum
synonymous
11
clinvar
124
clinvar
2
clinvar
 137
missense
14
clinvar
30
clinvar
393
clinvar
8
clinvar
 445
nonsense
23
clinvar
8
clinvar
 31
start loss
0
frameshift
17
clinvar
12
clinvar
1
clinvar
 30
splice donor/acceptor (+/-2bp)
1
clinvar
11
clinvar
4
clinvar
 16
Total55614091322659

Highest pathogenic variant AF is 0.00006071653

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 35 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_003995.4RefSeqNP_003986.222MANE Select
ENST00000342694.7EnsemblENSP00000341083.222MANE Select
NM_001378923.1RefSeqNP_001365852.122Standard
ENST00000421267.6EnsemblENSP00000399204.210Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Oxytocin signaling pathway - Homo sapiens (human)
  • Vascular smooth muscle contraction - Homo sapiens (human)
  • Purine metabolism - Homo sapiens (human)
  • cGMP-PKG signaling pathway - Homo sapiens (human)
  • Physiological factors

Biological Process

  • ossification
  • cGMP biosynthetic process
  • protein phosphorylation
  • signal transduction
  • receptor guanylyl cyclase signaling pathway

Molecular Function

  • peptide receptor activity
  • guanylate cyclase activity
  • protein kinase activity
  • protein binding
  • ATP binding

Cellular Component

  • plasma membrane
  • integral component of plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000342694
Coding exons
22
Length
17579
Individuals with no LoFs
125717
Homozygous LoFs
0
Heterozygous LoFs
31
Defined
125748
p
0.000123
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense2.963986020.6610.00004106760
Missense (PolyPhen)94197.840.475132323
Synonymous0.4612232320.9620.00001382197
Loss of Function4.541854.00.3330.00000360580

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000190.00018rare
Latino/Admixed American0.000140.00014rare
Ashkenazi Jewish00.0absent
East Asian0.0000540.000054rare
Finnish0.000140.00014rare
European (Non-Finnish)0.000110.00011rare
South Asian0.000200.00020rare
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Receptor for the C-type natriuretic peptide NPPC/CNP hormone. Has guanylate cyclase activity upon binding of its ligand. May play a role in the regulation of skeletal growth. {ECO:0000269|PubMed:15146390, ECO:0000269|PubMed:1672777, ECO:0000269|PubMed:24001744, ECO:0000269|PubMed:24471569, ECO:0000269|PubMed:26980729}.;
Disease
DISEASE: Acromesomelic dysplasia, Maroteaux type (AMDM) [MIM:602875]: An autosomal recessive acromesomelic chondrodysplasia. Acromesomelic chondrodysplasias are rare hereditary skeletal disorders characterized by short stature, very short limbs and hand/foot malformations. The severity of limb abnormalities increases from proximal to distal with profoundly affected hands and feet showing brachydactyly and/or rudimentary fingers (knob-like fingers). AMDM is characterized by axial skeletal involvement with wedging of vertebral bodies. In AMDM all skeletal elements are present but show abnormal rates of linear growth. {ECO:0000269|PubMed:15146390, ECO:0000269|PubMed:17652215, ECO:0000269|PubMed:26980729}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Epiphyseal chondrodysplasia, Miura type (ECDM) [MIM:615923]: An overgrowth syndrome characterized by tall stature, long hands and feet with arachnodactyly, macrodactyly of the great toes, scoliosis, coxa valga and slipped capital femoral epiphysis. {ECO:0000269|PubMed:22870295, ECO:0000269|PubMed:23827346, ECO:0000269|PubMed:24057292, ECO:0000269|PubMed:24259409}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Short stature with non-specific skeletal abnormalities (SNSK) [MIM:616255]: A condition characterized by short stature, defined as a height less than 2 SD below normal, and no endocrine abnormalities. {ECO:0000269|PubMed:24001744, ECO:0000269|PubMed:24471569}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.266

Intolerance Scores

LoFtool
0.202
RVIS EVS
-1.04
RVIS percentile EVS
7.71

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.944

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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