MAB21L2
protein-codingmab-21 like 2, the group of MAB21 family
Gene summary
This gene is similar to the C. elegans MAB-21 cell fate-determining gene, a downstream target of transforming growth factor-beta signaling. It is thought that this gene may be involved in neural development. The protein encoded by this gene is primarily nuclear, although some cytoplasmic localization has been observed. [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 ~2.5 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0014380
Submitter: ClinGen
The MAB21L2 gene is located on chromosome 4 at 4q31.3 and is similar to C. elegans MAB-21 cell fate-determining gene, a downstream target of transforming growth factor-beta signaling. It is thought that this gene may be involved in neural development. MAB21L2 was first reported in relation to autosomal dominant Microphthalmia/Coloboma-Rhizomelic Dysplasia syndrome in 2014 (Rainger et al., PMID: 24906020). Other ophthalmic abnormalities reported in affected probands include anophthalmia, cataracts, and microcornea. Skeletal features reported in affected probands include recurrent dislocation of the patella, syndactyly, and joint contractures. The condition is also associated with intellectual disability/autism. Phenotypic variability is reported. Four missense, three nonsense variants, and one start loss variant that have been reported in nine probands in six publications (PMIDs: 34008892, 32830442, 29450879, 24906020, 25719200, 32737437) are included in this curation. The maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity appears to be loss of function but some pathogenic variants have been shown to have an increase in stability/activating effect. Residues 49-52 of MAB21L2 appear to be particularly important to the protein function. This gene-disease relationship is also supported by experimental evidence including a mouse model, a zebrafish model, and expression evidence (PMIDs: 30375740, 25719200, 30073347). The mutant mice show high phenotypic specificity with eye and skeletal anomalies. In summary, there is definitive evidence supporting the relationship between MAB21L2 and autosomal dominant Microphthalmia/Coloboma-Rhizomelic Dysplasia Syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Syndromic Disorders GCEP on the meeting date September 6, 2023 (SOP Version 9).
Inheritance Pattern: AD
Disease ID:MONDO:0014380
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0014380
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0014380
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0016073
Submitter: Ambry Genetics
Inheritance Pattern: SD
Disease ID:MONDO:0014380
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0014380
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0014380
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0014380
Submitter: G2P
Clinical Genomic Database (CGD)
Manifestation: Craniofacial; Musculoskeletal; Neurologic; Ophthalmologic
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 MAB21L2 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_006439.5. 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 | 3 | 15 | 1 | 19 | ||
| missense | 1 | 3 | 33 | 3 | 40 | |
| nonsense | 2 | 1 | 3 | 6 | ||
| start loss | 1 | 1 | ||||
| frameshift | 1 | 6 | 7 | |||
| splice donor/acceptor (+/-2bp) | 0 | |||||
| Total | 3 | 6 | 45 | 18 | 1 | 73 |
Highest pathogenic variant AF is 6.8479926e-7
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_006430.1 | 1 | MANE Select | |
| Ensembl | ENSP00000324701.4 | 1 | MANE Select |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| mab21l2 | Danio rerio | Structure: hyaloid vessel Quality: increased thickness abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Biological Process
- eye development
- nervous system development
- positive regulation of cell population proliferation
- embryonic body morphogenesis
- camera-type eye development
Molecular Function
- protein binding
Cellular Component
- nucleus
- cytoplasm
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000317605
- Coding exons
- 1
- Length
- 2767
- Individuals with no LoFs
- 0
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 0
- Defined
- 0
- p
- 0.00
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 2.96 | 110 | 238 | 0.461 | 0.0000152 | 2315 |
| Missense (PolyPhen) | 33 | 91.381 | 0.36113 | 863 | ||
| Synonymous | 1.53 | 94 | 115 | 0.818 | 0.00000828 | 749 |
| Loss of Function | 2.74 | 3 | 14.1 | 0.213 | 7.98e-7 | 135 |
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 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0 | 0.0 | absent |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Required for several aspects of embryonic development including normal development of the eye. {ECO:0000269|PubMed:24906020, ECO:0000269|PubMed:25719200}.;
- Disease
- DISEASE: Microphthalmia/coloboma and skeletal dysplasia syndrome (MCSKS) [MIM:615877]: A disease characterized by bilateral colobomatous microphthalmia or bilateral anophthalmia, associated with skeletal dysplasia in some cases. Additional ocular findings include microcornea, cataracts, corectopia and nystagmus. Intellectual disability is present in some patients. {ECO:0000269|PubMed:24906020, ECO:0000269|PubMed:25719200}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.130
Intolerance Scores
- LoFtool
- 0.221
- RVIS EVS
- -0.34
- RVIS percentile EVS
- 30.07
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 |