GeneBe

BMP2

protein-coding

bone morphogenetic protein 2, the group of Bone morphogenetic proteins

Gene summary

This gene encodes a secreted ligand of the TGF-beta (transforming growth factor-beta) superfamily of proteins. Ligands of this family bind various TGF-beta receptors leading to recruitment and activation of SMAD family transcription factors that regulate gene expression. The encoded preproprotein is proteolytically processed to generate each subunit of the disulfide-linked homodimer, which plays a role in bone and cartilage development. Duplication of a regulatory region downstream of this gene causes a form of brachydactyly characterized by a malformed index finger and second toe in human patients. [provided by RefSeq, Jul 2016]

Previous symbols:
  • BMP2A

MANE transcript

NM_001200.4

Inheritance

AD

ClinVar variants

P:39U:152B:56

Top phenotype

Short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies 1

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chr20:6,767,686-6,780,246

External References & Databases

Ensembl (ENSG00000125845)NCBI Gene (650)OMIM (112261)HGNC:1069GenCCUniProt (P12643)AlphaFoldClinVar (BMP2)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~12.6 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0100297

Submitter: G2P

short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0100297

Submitter: PanelApp Australia

short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0100297

Submitter: Labcorp Genetics (formerly Invitae)

brachydactyly type A2SUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007216

Submitter: Orphanet

brachydactyly type A2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007216

Submitter: PanelApp Australia

brachydactyly type A2LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0007216

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies 1AD

Manifestation: Cardiovascular; Craniofacial; Musculoskeletal

Intervention: Cardiovascular

Rationale: Among other features, the condition can involve arrhythmias, and awareness can allow early diagnosis and management

Comments: Brachydactyly, type A2 involves duplication of a downstream regulatory element of the gene

Refs: 7390514; 19327734; 21357617; 29198724Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to BMP2 variants in ClinVar

14 Conditions Cataloged
not providedTotal: 191
Inborn genetic diseasesTotal: 50
Short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies 1Total: 22
BMP2-related disorderTotal: 21
not specifiedTotal: 17
Short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomaliesTotal: 7
Type A2 brachydactylyTotal: 3
PDA1Total: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001200.4. 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
1
clinvar
48
clinvar
 49
missense
3
clinvar
1
clinvar
148
clinvar
8
clinvar
 160
nonsense
5
clinvar
12
clinvar
1
clinvar
 18
start loss
1
clinvar
 1
frameshift
6
clinvar
9
clinvar
1
clinvar
 16
splice donor/acceptor (+/-2bp)
2
clinvar
1
clinvar
 3
Total1623152560247

Highest pathogenic variant AF is 6.846811e-7

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 10 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_001200.4RefSeqNP_001191.12MANE Select
ENST00000378827.5EnsemblENSP00000368104.32MANE Select
ENST00000936876.1EnsemblENSP00000606935.12Standard
ENST00000936876.2EnsemblENSP00000606935.12Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
bmp2bDanio rerio

Structure: erythroid lineage cell

Quality: absent

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • TGF-beta signaling pathway - Homo sapiens (human)
  • Basal cell carcinoma - Homo sapiens (human)
  • Hippo signaling pathway - Homo sapiens (human)
  • Pathways in cancer - Homo sapiens (human)
  • Cytokine-cytokine receptor interaction - Homo sapiens (human)

Biological Process

  • negative regulation of transcription by RNA polymerase II
  • activation of MAPK activity
  • skeletal system development
  • osteoblast differentiation
  • branching involved in ureteric bud morphogenesis

Molecular Function

  • retinol dehydrogenase activity
  • signaling receptor binding
  • cytokine activity
  • transforming growth factor beta receptor binding
  • protein binding

Cellular Component

  • extracellular region
  • extracellular space
  • cell surface
  • intracellular membrane-bounded organelle
  • BMP receptor complex

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000378827
Coding exons
2
Length
12617
Individuals with no LoFs
0
Homozygous LoFs
0
Heterozygous LoFs
0
Defined
0
p
0.00
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense1.141882370.7920.00001282586
Missense (PolyPhen)78137.080.569021520
Synonymous-0.49710497.81.060.00000567793
Loss of Function3.38013.30.007.39e-7148

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American00.0absent
Ashkenazi Jewish00.0absent
East Asian00.0absent
Finnish00.0absent
European (Non-Finnish)00.0absent
South Asian00.0absent
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Induces cartilage and bone formation (PubMed:3201241). Stimulates the differentiation of myoblasts into osteoblasts via the EIF2AK3-EIF2A- ATF4 pathway. BMP2 activation of EIF2AK3 stimulates phosphorylation of EIF2A which leads to increased expression of ATF4 which plays a central role in osteoblast differentiation. In addition stimulates TMEM119, which upregulates the expression of ATF4 (PubMed:24362451). {ECO:0000269|PubMed:24362451, ECO:0000269|PubMed:3201241}.;
Disease
DISEASE: Short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies (SSFSC) [MIM:617877]: An autosomal dominant disorder characterized by short stature, facial dysmorphism, skeletal anomalies, and variable cardiac defects. Distinctive facial features include midface retrusion, short upturned nose, long philtrum, high-arched or cleft palate, and variable degrees of micrognathia and dental crowding. Skeletal anomalies include patterning defects of the axial skeleton, characterized by 11 pairs of ribs and brachydactyly of the fifth ray. Congenital heart defects are variably observed and appear to involve primarily the cardiac outflow tract. {ECO:0000269|PubMed:29198724}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.775

Intolerance Scores

RVIS EVS
-0.27
RVIS percentile EVS
34.6

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.937

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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