GREM2
protein-codinggremlin 2, DAN family BMP antagonist, the group of DAN family
Gene summary
This gene encodes a member of the BMP (bone morphogenic protein) antagonist family. Like BMPs, BMP antagonists contain cystine knots and typically form homo- and heterodimers. The CAN (cerberus and dan) subfamily of BMP antagonists, to which this gene belongs, is characterized by a C-terminal cystine knot with an eight-membered ring. The antagonistic effect of the secreted glycosylated protein encoded by this gene is likely due to its direct binding to BMP proteins. As an antagonist of BMP, this gene may play a role in regulating organogenesis, body patterning, and tissue differentiation. [provided by RefSeq, Jul 2008]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~122.6 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0014999
Submitter: ClinGen
*GREM2* was reported in connection with autosomal dominant tooth agenesis selective 9 in 2015 (Kantaputra et al., 2015 PMID: 26416033). Patients with condition present with dental anomalies such as isolated tooth agenesis, microdontia, short tooth roots and, taurodontism. Additional clinical features include sparse and slow-growing hair, and dry and itchy skin. 3 missense variants from 2 publications have been included in this curation (PMIDs: 26416033, 28992378). The mechanism of pathogenicity is unclear. One mutation generates a hypermorphic allele with an increased inhibitory activity while the impact of other mutations must be further investigated. This gene-disease pair is also supported by expression studies, protein interaction assays, and a mouse model (PMIDs: 24686385, 26416033, 19073177, 15039429). 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. This classification was approved by the Craniofacial Malformations Gene Curation Expert Panel on the meeting date 01/16/2025 (SOP Version 11)
Clinical Genomic Database (CGD)
Manifestation: Dental; Dermatologic
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
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to GREM2 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_022469.4. 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 | 1 | 1 | ||||
| missense | 1 | 1 | 21 | 23 | ||
| nonsense | 0 | |||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 0 | |||||
| Total | 1 | 1 | 21 | 1 | 0 | 24 |
Highest pathogenic variant AF is 0.00004904584
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_071914.3 | 1 | MANE Select | |
| Ensembl | ENSP00000318650.4 | 1 | MANE Select | |
| Ensembl | ENSP00000529963.1 | 1 | Standard | |
| Ensembl | ENSP00000529963.1 | 1 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| grem2b | Danio rerio | Structure: pharyngeal arch 1 Quality: malformed abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Signal Transduction
- BMP Signalling Pathway
- Signaling by BMP
- Signaling by TGF-beta family members
Biological Process
- embryonic body morphogenesis
- cytokine-mediated signaling pathway
- BMP signaling pathway
- sequestering of BMP from receptor via BMP binding
- determination of dorsal identity
Molecular Function
- cytokine activity
- heparin binding
- BMP binding
- protein homodimerization activity
Cellular Component
- extracellular region
- extracellular space
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000318160
- Coding exons
- 1
- Length
- 122577
- Individuals with no LoFs
- 125617
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 3
- Defined
- 125620
- p
- 0.0000119
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.23 | 78 | 115 | 0.677 | 0.00000789 | 1089 |
| Missense (PolyPhen) | 20 | 35.743 | 0.55956 | 355 | ||
| Synonymous | 1.38 | 42 | 55.1 | 0.763 | 0.00000403 | 335 |
| Loss of Function | 1.15 | 3 | 6.07 | 0.494 | 3.11e-7 | 62 |
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 | 0.000054 | 0.000054 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000018 | 0.000018 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Cytokine that inhibits the activity of BMP2 and BMP4 in a dose-dependent manner, and thereby modulates signaling by BMP family members. Contributes to the regulation of embryonic morphogenesis via BMP family members. Antagonizes BMP4-induced suppression of progesterone production in granulosa cells. {ECO:0000250|UniProtKB:O88273}.;
- Disease
- DISEASE: Tooth agenesis, selective, 9 (STHAG9) [MIM:617275]: A form of selective tooth agenesis, a common anomaly characterized by the congenital absence of one or more teeth. Selective tooth agenesis without associated systemic disorders has sometimes been divided into 2 types: oligodontia, defined as agenesis of 6 or more permanent teeth, and hypodontia, defined as agenesis of less than 6 teeth. The number in both cases does not include absence of third molars (wisdom teeth). STHAG9 inheritance is autosomal dominant. {ECO:0000269|PubMed:26416033}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.149
Intolerance Scores
- LoFtool
- 0.368
- RVIS EVS
- 0.13
- RVIS percentile EVS
- 62.74
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.307
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |