NPR2

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

Basic information

Region (hg38): 9:35791003-35809732

Previous symbols: [ "ANPRB", "NPRB", "AMDM" ]

Links

ENSG00000159899 ∙ NCBI:4882 ∙ OMIM:108961 ∙ HGNC:7944 ∙ Uniprot:P20594 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• acromesomelic dysplasia 1, Maroteaux type (Definitive), mode of inheritance: AR
• acromesomelic dysplasia 1, Maroteaux type (Definitive), mode of inheritance: AR
• tall stature-scoliosis-macrodactyly of the great toes syndrome (Moderate), mode of inheritance: AD
• short stature with nonspecific skeletal abnormalities (Moderate), mode of inheritance: AD
• acromesomelic dysplasia 1, Maroteaux type (Supportive), mode of inheritance: AR
• tall stature-scoliosis-macrodactyly of the great toes syndrome (Supportive), mode of inheritance: AD
• acromesomelic dysplasia 1, Maroteaux type (Strong), mode of inheritance: AR
• tall stature-scoliosis-macrodactyly of the great toes syndrome (Strong), mode of inheritance: AD
• short stature with nonspecific skeletal abnormalities (Strong), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Epiphyseal chondrodysplasia, Miura type; Short stature with nonspecific skeletal abnormalities; Acromesomelic dysplasia 1	AD/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	Musculoskeletal	15146390; 16384845; 22691581; 22870295; 24001744; 24057292; 24259409; 24471569; 26336901; 26537434

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the NPR2 gene.

• Acromesomelic dysplasia 1, Maroteaux type;Tall stature-scoliosis-macrodactyly of the great toes syndrome (20 variants)
• Acromesomelic dysplasia 1, Maroteaux type (17 variants)
• not provided (3 variants)
• Tall stature-scoliosis-macrodactyly of the great toes syndrome;Acromesomelic dysplasia 1, Maroteaux type (2 variants)
• NPR2-related disorder (2 variants)
• Short stature with nonspecific skeletal abnormalities (2 variants)
• Epilepsy, familial focal, with variable foci 2 (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the NPR2 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			12	71	5	88
missense	7	13	231	3		254
nonsense	19	6				25
start loss						0
frameshift	9	5				14
inframe indel			2			2
splice donor/acceptor (+/-2bp)	2	5	1			8
splice region		1	9	9	1	20
non coding			7	37	15	59
Total	37	29	253	111	20

Highest pathogenic variant AF is 0.0000131

Variants in NPR2

This is a list of pathogenic ClinVar variants found in the NPR2 region.

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

Position	Type	Phenotype	Significance	ClinVar
9-35792191-C-T			Benign (Jun 20, 2021)
9-35792415-C-T		Acromesomelic dysplasia 1, Maroteaux type;Tall stature-scoliosis-macrodactyly of the great toes syndrome	Likely benign (Sep 08, 2023)
9-35792417-G-A		Acromesomelic dysplasia 1, Maroteaux type;Tall stature-scoliosis-macrodactyly of the great toes syndrome	Likely benign (Jun 27, 2022)
9-35792419-C-T		Tall stature-scoliosis-macrodactyly of the great toes syndrome;Acromesomelic dysplasia 1, Maroteaux type	Uncertain significance (Jul 17, 2022)
9-35792422-C-A		Acromesomelic dysplasia 1, Maroteaux type	Pathogenic (Apr 20, 2020)
9-35792426-T-C		Acromesomelic dysplasia 1, Maroteaux type • Acromesomelic dysplasia 1, Maroteaux type;Tall stature-scoliosis-macrodactyly of the great toes syndrome	Benign (Jan 31, 2024)
9-35792444-C-T		Acromesomelic dysplasia 1, Maroteaux type;Tall stature-scoliosis-macrodactyly of the great toes syndrome	Likely benign (Feb 20, 2023)
9-35792465-TC-T		Acromesomelic dysplasia 1, Maroteaux type;Tall stature-scoliosis-macrodactyly of the great toes syndrome	Pathogenic (Dec 29, 2021)
9-35792468-C-T		Acromesomelic dysplasia 1, Maroteaux type;Tall stature-scoliosis-macrodactyly of the great toes syndrome	Likely benign (Apr 25, 2023)
9-35792471-G-A		Acromesomelic dysplasia 1, Maroteaux type;Tall stature-scoliosis-macrodactyly of the great toes syndrome	Likely benign (Jan 22, 2024)
9-35792472-G-T		not specified • Acromesomelic dysplasia 1, Maroteaux type;Tall stature-scoliosis-macrodactyly of the great toes syndrome;Short stature with nonspecific skeletal abnormalities • Acromesomelic dysplasia 1, Maroteaux type;Tall stature-scoliosis-macrodactyly of the great toes syndrome • NPR2-related disorder	Conflicting classifications of pathogenicity (Jan 22, 2024)
9-35792473-C-T		Acromesomelic dysplasia 1, Maroteaux type;Tall stature-scoliosis-macrodactyly of the great toes syndrome	Uncertain significance (Jul 11, 2022)
9-35792493-G-A		Acromesomelic dysplasia 1, Maroteaux type;Tall stature-scoliosis-macrodactyly of the great toes syndrome	Uncertain significance (Jun 05, 2022)
9-35792498-G-A		Acromesomelic dysplasia 1, Maroteaux type;Tall stature-scoliosis-macrodactyly of the great toes syndrome • Acromesomelic dysplasia 1, Maroteaux type	Conflicting classifications of pathogenicity (Oct 19, 2023)
9-35792502-C-A		Acromesomelic dysplasia 1, Maroteaux type	Pathogenic (Jul 01, 2004)
9-35792506-A-C		Acromesomelic dysplasia 1, Maroteaux type	Uncertain significance (Jan 12, 2018)
9-35792532-T-TGTGGC		Acromesomelic dysplasia 1, Maroteaux type	Pathogenic (Apr 01, 2022)
9-35792535-C-G		Acromesomelic dysplasia 1, Maroteaux type;Tall stature-scoliosis-macrodactyly of the great toes syndrome	Uncertain significance (Aug 09, 2022)
9-35792538-C-T		Acromesomelic dysplasia 1, Maroteaux type	Uncertain significance (-)
9-35792548-C-T			Likely pathogenic (Aug 18, 2015)
9-35792550-G-A			Uncertain significance (Nov 18, 2022)
9-35792562-G-A			Uncertain significance (Nov 30, 2019)
9-35792563-C-A		Acromesomelic dysplasia 1, Maroteaux type;Tall stature-scoliosis-macrodactyly of the great toes syndrome	Uncertain significance (Aug 14, 2022)
9-35792578-G-C		Inborn genetic diseases • Acromesomelic dysplasia 1, Maroteaux type;Tall stature-scoliosis-macrodactyly of the great toes syndrome	Uncertain significance (Feb 21, 2022)
9-35792579-C-A		Acromesomelic dysplasia 1, Maroteaux type;Tall stature-scoliosis-macrodactyly of the great toes syndrome	Likely benign (Jun 20, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
NPR2	protein_coding	protein_coding	ENST00000342694	22	17579

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.0000420	1.00	125717	0	31	125748	0.000123

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.96	398	602	0.661	0.0000410	6760
Missense in Polyphen		94	197.84	0.47513		2323
Synonymous	0.461	223	232	0.962	0.0000138	2197
Loss of Function	4.54	18	54.0	0.333	0.00000360	580

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000330	0.000329
Ashkenazi Jewish	0.00	0.00
East Asian	0.0000544	0.0000544
Finnish	0.000139	0.000139
European (Non-Finnish)	0.000115	0.000114
Middle Eastern	0.0000544	0.0000544
South Asian	0.000196	0.000196
Other	0.00	0.00

dbNSFP

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.
• Pathway: 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;Purine metabolism;Cardiac conduction;Muscle contraction;Purine nucleotides nucleosides metabolism (Consensus)

Recessive Scores

• pRec: 0.266

Intolerance Scores

• loftool: 0.202
• rvis_EVS: -1.04
• rvis_percentile_EVS: 7.71

Haploinsufficiency Scores

• pHI: 0.200
• hipred: Y
• hipred_score: 0.708
• ghis: 0.618

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.944

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Npr2
• Phenotype: homeostasis/metabolism phenotype; muscle phenotype; craniofacial phenotype; growth/size/body region phenotype; endocrine/exocrine gland phenotype; respiratory system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); immune system phenotype; skeleton phenotype; limbs/digits/tail 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); digestive/alimentary phenotype; reproductive system phenotype; 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)

Gene ontology

• Biological process: ossification;cGMP biosynthetic process;protein phosphorylation;signal transduction;receptor guanylyl cyclase signaling pathway;regulation of blood pressure;positive regulation of cGMP-mediated signaling;cGMP-mediated signaling;reproductive process;negative regulation of meiotic cell cycle;bone development;cellular response to granulocyte macrophage colony-stimulating factor stimulus;negative regulation of oocyte maturation;regulation of cardiac conduction
• Cellular component: plasma membrane;integral component of plasma membrane
• Molecular function: peptide receptor activity;guanylate cyclase activity;protein kinase activity;protein binding;ATP binding;GTP binding;natriuretic peptide receptor activity;peptide hormone binding;hormone binding;identical protein binding