MAML2
protein-codingmastermind like transcriptional coactivator 2
Gene summary
The protein encoded by this gene is a member of the Mastermind-like family of proteins. All family members are proline and glutamine-rich, and contain a conserved basic domain that binds the ankyrin repeat domain of the intracellular domain of the Notch receptors (ICN1-4) in their N-terminus, and a transcriptional activation domain in their C-terminus. This protein binds to an extended groove that is formed by the interaction of CBF1, Suppressor of Hairless, LAG-1 (CSL) with ICN, and positively regulates Notch signaling. High levels of expression of this gene have been observed in several B cell-derived lymphomas. Translocations resulting in fusion proteins with both CRTC1 and CRTC3 have been implicated in the development of mucoepidermoid carcinomas, while a translocation event with CXCR4 has been linked with chronic lymphocytic leukemia (CLL). Copy number variation in the polyglutamine tract has been observed. [provided by RefSeq, Jan 2015]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~366.6 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: Unknown
Disease ID:MONDO:0005453
Submitter: ClinGen
*MAML2* is a transcriptional coactivator for NOTCH proteins and hypothesized to be related to congenital heart defects. No evidence for a causal role for *MAML2* in congenital heart disease has been reported. More evidence is needed to either support or entirely refute the role *MAML2* plays in this disease. This classification was approved by the ClinGen Congenital Heart Disease GCEP on the meeting date 9/3/2024 (SOP version 10).
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to MAML2 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_032427.4. 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 | 4 | 2 | 6 | |||
| missense | 144 | 4 | 2 | 150 | ||
| nonsense | 2 | 2 | ||||
| start loss | 0 | |||||
| frameshift | 2 | 2 | ||||
| splice donor/acceptor (+/-2bp) | 0 | |||||
| Total | 0 | 0 | 152 | 6 | 2 | 160 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_115803.1 | 5 | MANE Select | |
| Ensembl | ENSP00000434552.1 | 5 | MANE Select | |
| Ensembl | ENSP00000813799.1 | 5 | Standard | |
| RefSeq | XP_011541325.1 | 5 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Th1 and Th2 cell differentiation - Homo sapiens (human)
- Notch signaling pathway - Homo sapiens (human)
- Human papillomavirus infection - Homo sapiens (human)
- NOTCH-Ncore
- Canonical and Non-canonical Notch signaling
Biological Process
- transcription initiation from RNA polymerase II promoter
- Notch signaling pathway
- positive regulation of transcription of Notch receptor target
- positive regulation of Notch signaling pathway
- positive regulation of transcription by RNA polymerase II
Molecular Function
- transcription coactivator activity
Cellular Component
- nucleus
- nucleoplasm
- nuclear speck
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000524717
- Coding exons
- 5
- Length
- 366583
- Individuals with no LoFs
- 124671
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 9
- Defined
- 124680
- p
- 0.0000361
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.450 | 584 | 615 | 0.949 | 0.0000309 | 7580 |
| Missense (PolyPhen) | 97 | 95.577 | 1.0149 | 1123 | ||
| Synonymous | -0.755 | 249 | 234 | 1.06 | 0.0000122 | 2261 |
| Loss of Function | 5.91 | 6 | 51.9 | 0.116 | 0.00000273 | 487 |
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) | 0.000065 | 0.000062 | rare |
| South Asian | 0.000065 | 0.000065 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Acts as a transcriptional coactivator for NOTCH proteins. Has been shown to amplify NOTCH-induced transcription of HES1. Potentiates activation by NOTCH3 and NOTCH4 more efficiently than MAML1 or MAML3. {ECO:0000269|PubMed:12370315, ECO:0000269|PubMed:12386158, ECO:0000269|PubMed:12539049}.;
- Disease
- DISEASE: Note=A chromosomal aberration involving MAML2 is found in mucoepidermoid carcinomas, benign Warthin tumors and clear cell hidradenomas. Translocation t(11;19)(q21;p13) with CRTC1. The fusion protein consists of the N-terminus of CRTC1 joined to the C-terminus of MAML2. The reciprocal fusion protein consisting of the N-terminus of MAML2 joined to the C-terminus of CRTC1 has been detected in a small number of mucoepidermoid carcinomas. {ECO:0000269|PubMed:15729701}.;
Recessive Scores
- pRec
- 0.134
Intolerance Scores
- RVIS EVS
- 0.21
- RVIS percentile EVS
- 67.52
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.991
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |