GeneBe

BMPR2

protein-coding

bone morphogenetic protein receptor type 2, the group of Type 2 receptor serine/threonine kinases

Gene summary

This gene encodes a member of the bone morphogenetic protein (BMP) receptor family of transmembrane serine/threonine kinases. The ligands of this receptor are members of the TGF-beta superfamily. BMPs are involved in endochondral bone formation and embryogenesis. These proteins transduce their signals through the formation of heteromeric complexes of two different types of serine (threonine) kinase receptors: type I receptors of about 50-55 kD and type II receptors of about 70-80 kD. Mutations in this gene have been associated with primary pulmonary hypertension, both familial and fenfluramine-associated, and with pulmonary venoocclusive disease. [provided by RefSeq, May 2020]

Previous symbols:
  • PPH1

MANE transcript

NM_001204.7

Inheritance

AD

ClinVar variants

P:513U:878B:526

Top phenotype

Pulmonary hypertension, primary 1; Pulmonary venoocclusive disease 1

gnomAD constraint

pLI —, LoF o/e 0.08

Max pathogenic AF

—

Genomic locus

chr2:202,376,327-202,567,751

External References & Databases

Ensembl (ENSG00000204217)NCBI Gene (659)OMIM (600799)HGNC:1078GenCCUniProt (Q13873)AlphaFoldClinVar (BMPR2)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~191.4 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

pulmonary hypertension, primary, 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0024533

Submitter: PanelApp Australia

primary ovarian failureLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0005387

Submitter: PanelApp Australia

heritable pulmonary arterial hypertensionSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0017148

Submitter: Orphanet

pulmonary venoocclusive disease 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0020713

Submitter: PanelApp Australia

pulmonary hypertension, primary, 1DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0024533

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.

pulmonary arterial hypertensionDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015924

Submitter: ClinGen

BMPR2 was first reported in relation to autosomal dominant pulmonary arterial hypertension in 2000 (Deng et al PMID:10903931 and The International PPH Consortium PMID:10973254). More than 500 unique variants (missense, in-frame indel, nonsense, frameshift, large deletions) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level, case-control, segregation and experimental data. Summary of case-level data: 12 points. Variants in this gene have been reported in at least 16 probands in 2 publications (PMID:10903931, PMID:10973254). Variants in this gene segregated with disease in 10 additional family members. More evidence is available in the literature but the maximum score for genetic evidence (12 points) has been reached. The mechanism is haploinsufficiency (PMID:11115378, PMID: 16429395). Summary of experimental data: 6 points. This gene-disease association is supported by expression, biochemical, in vitro functional and animal model data. In summary, BMPR2 is definitively associated with autosomal dominant pulmonary arterial hypertension. This has been repeatedly demonstrated in both research and diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen PH Working Group on Sept 9, 2020.

congenital heart diseaseLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0005453

Submitter: ClinGen

*BMPR2* was first reported in relation to autosomal dominant congenital heart disease in 2016 (Liu et al., PMID: 27002414; Sicko et al., PMID: 27788187). Another publication in 2012 reported a paternally inherited deletion at 2q33.1 of about 34 kb, falling into the first intron of the *BMPR2* (PMID: 21457232). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism, inheritance pattern, and phenotypic variability. Therefore, congenital heart disease, Ebstein anomaly, and conotruncal defects have been lumped into one disease entity. One proband with a noncanonical splice-site variant is included in this curation (PMID: 27002414). At least eight other unique variants (missense, frameshifts, splice site) reported in five probands in five publications were not scored due to their high minor allele frequency (> 0.00001) in gnomAD v2.1.1 or a low REVEL score (PMIDs: 27788187, 27002414, 28991257, 33448881, 35910219). The gene-disease relationship is supported by two mouse models and expression data (PMIDs: 23352489, 12441304, 19409885). 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. Of note, *BMPR2* has been classified as definitive for autosomal dominant pulmonary arterial hypertension by the Pulmonary Hypertension GCEP in December 2020. This classification was approved by the ClinGen Congenital Heart Disease GCEP on the meeting date 9/11/2023 (SOP Version 9).

pulmonary hypertension, primary, 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0024533

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Pulmonary hypertension, primary 1; Pulmonary venoocclusive disease 1AD

Manifestation: Cardiovascular; Pulmonary

Intervention: Cardiovascular; Pharmacogenomic; Pulmonary

Rationale: While prognosis is overall poor, medical therapy (eg, with calcium antagonists, anticoagulants, prostanoids, endothelin receptor antagonists, etc.) may be beneficial, though heart/lung transplantation may be required; Control of complications may be beneficial; Exposure to agents such as fenfluramine has been described as greatly increasing the risk of disease

Refs: 601742; 1863023; 10903931; 11115457; 10973254; 11015450; 12358323; 12446270; 16429403; 16429395; 15965979; 18356561; 20956135; 19749199; 19713419; 19555857; 21801371Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to BMPR2 variants in ClinVar

30 Conditions Cataloged
Inborn genetic diseasesTotal: 1178
Pulmonary hypertension, primary, 1Total: 513
Primary pulmonary hypertensionTotal: 491
Pulmonary arterial hypertensionTotal: 243
Pulmonary venoocclusive disease 1Total: 150
not providedTotal: 132
Idiopathic and/or familial pulmonary arterial hypertensionTotal: 61
BMPR2-related disorderTotal: 16

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001204.7. 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
3
clinvar
6
clinvar
417
clinvar
 426
missense
67
clinvar
34
clinvar
853
clinvar
101
clinvar
8
clinvar
 1063
nonsense
104
clinvar
11
clinvar
5
clinvar
 120
start loss
1
clinvar
 1
frameshift
216
clinvar
14
clinvar
9
clinvar
 239
splice donor/acceptor (+/-2bp)
32
clinvar
31
clinvar
5
clinvar
 68
Total4229187851881917

Highest pathogenic variant AF is 0.000040929775

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 15 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_001204.7RefSeqNP_001195.213MANE Select
ENST00000374580.10EnsemblENSP00000363708.413MANE Select
ENST00000374574.2EnsemblENSP00000363702.212Standard
ENST00000374574.3EnsemblENSP00000363702.212Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
bmpr2bDanio rerio

Structure: thoracic duct

Quality: has fewer parts of type

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • TGF-beta signaling pathway - Homo sapiens (human)
  • Axon guidance - Homo sapiens (human)
  • Signaling pathways regulating pluripotency of stem cells - Homo sapiens (human)
  • Hippo signaling pathway - Homo sapiens (human)
  • Fluid shear stress and atherosclerosis - Homo sapiens (human)

Biological Process

  • mesoderm formation
  • maternal placenta development
  • endothelial cell proliferation
  • positive regulation of endothelial cell proliferation
  • lymphangiogenesis

Molecular Function

  • transforming growth factor beta-activated receptor activity
  • transforming growth factor beta receptor activity, type II
  • protein binding
  • ATP binding
  • activin receptor activity, type II

Cellular Component

  • extracellular space
  • nucleoplasm
  • cytoplasm
  • plasma membrane
  • integral component of plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000374580
Coding exons
13
Length
190816
Individuals with no LoFs
125739
Homozygous LoFs
0
Heterozygous LoFs
9
Defined
125748
p
0.0000358
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense2.064295670.7560.00002986810
Missense (PolyPhen)110211.730.519542568
Synonymous1.921652000.8270.000009922054
Loss of Function5.88447.90.08350.00000289525

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American00.0absent
Ashkenazi Jewish00.0absent
East Asian00.0absent
Finnish00.0absent
European (Non-Finnish)0.0000700.000070rare
South Asian0.0000330.000033rare
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: On ligand binding, forms a receptor complex consisting of two type II and two type I transmembrane serine/threonine kinases. Type II receptors phosphorylate and activate type I receptors which autophosphorylate, then bind and activate SMAD transcriptional regulators. Binds to BMP7, BMP2 and, less efficiently, BMP4. Binding is weak but enhanced by the presence of type I receptors for BMPs. Mediates induction of adipogenesis by GDF6. {ECO:0000250|UniProtKB:O35607}.;
Disease
DISEASE: Pulmonary venoocclusive disease 1, autosomal dominant (PVOD1) [MIM:265450]: A disease characterized by widespread fibrous obstruction and intimal thickening of septal veins and preseptal venules, a low diffusing capacity for carbon monoxide, occult alveolar hemorrhage, and nodular ground-glass opacities, septal lines and lymph node enlargement showed by high-resolution computed tomography of the chest. It is frequently associated with pulmonary capillary dilatation and proliferation, and is a rare and devastating cause of pulmonary hypertension. {ECO:0000269|PubMed:12446270, ECO:0000269|PubMed:16429395}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.501

Intolerance Scores

LoFtool
0.0515
RVIS EVS
-0.93
RVIS percentile EVS
9.61

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.998

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
Feedback | API | Annotate VCF | Sitemap | About | Privacy & Terms
For research and educational, non-commercial use only. Not for clinical or diagnostic use. GeneBe does not provide medical advice. Data use for AI modeling is prohibited: if used, the cost is $0.001 per byte of downloaded uncompressed data.