POMT2
protein-codingprotein O-mannosyltransferase 2, the group of Dolichyl D-mannosyl phosphate dependent mannosyltransferases
Gene summary
The protein encoded by this gene is an O-mannosyltransferase that requires interaction with the product of the POMT1 gene for enzymatic function. The encoded protein is found in the membrane of the endoplasmic reticulum. Defects in this gene are a cause of Walker-Warburg syndrome (WWS).[provided by RefSeq, Oct 2008]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~45.9 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0013162
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0700071
Submitter: ClinGen
POMT2 was first reported in relation to myopathies in 2004 (van Reeuwijk et al., PMID: 15894594). Over 50 unique variants (including missense, nonsense, and frameshift variants) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level genetic data and experimental data linking biallelic POMT2 loss of function to myopathy. Summary of Case-Level Data (12 points): Variants in this gene have been reported in over 70 probands with POMT2-related myopathy. The phenotypes described in these individuals range widely in severity and age of onset, with some patients exhibiting Walker-Warburg syndrome surviving only days or weeks beyond birth, while later onset has been reported in patients with milder limb-girdle muscular dystrophy with or without intellectual disability. At least 10 probands reported to date (PMID: 17923109; DOI: 10.1007/978-3-319-07500-6_17; PMID: 24183756; PMID: 30060766 Patients 20, 22, and 26; PMID: 29175898 Case 5; PMID: 29759639; DOI: 10.21203/rs.2.483/v1; PMID: 32576226 Patient 39) meet the LGMD GCEP criteria for isolated LGMD (progressive weakness in limb musculature (pelvic and shoulder girdle); independent ambulation by the age 2 years; elevated CK of >2X the ULN; muscle biopsy with dystrophic and myopathic features). Summary of Experimental Data (5.5 points): This gene-disease relationship is supported by expression studies, biochemical function studies, animal models, and rescue experiments in patient cells and Drosophila. The POMT2 protein is involved in the catalysis of the initiation step of the O-mannosyl glycosylation pathway on the mucin-like domain of α-dystroglycan. Defects in the glycosylation of α-dystroglycan disrupt dystroglycan binding to laminin-G domain-containing extracellular proteins in muscle and brain and are well-known to lead to dystroglycanopathies (PMID: 23929950). Loss of POMT2 in patient cells and Drosophila and mouse models leads to hallmark biochemical and phenotypic features, some of which have been mitigated by rescue (PMID: 29759639; PMID: 29167399; PMID: 15271988; PMID: 16219785; PMID: 20644630; PMID: 21452199; PMID: 21970971). In summary, POMT2 is definitively associated with autosomal recessive myopathies. 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 Neuromuscular Working Group on 9/14/2021 (SOP Version 7) and updated to SOP Version 8 on 11/2/2021. Lumping and Splitting Considerations: OMIM entities: autosomal recessive congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies type A2 (MIM: 613150); autosomal recessive congenital muscular dystrophy-dystroglycanopathy with mental retardation type B2 (MIM: 613156); autosomal recessive limb-girdle muscular dystrophy-dystroglycanopathy type C2 (MIM: 613158). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanisms AND inheritance pattern AND phenotypic variability in the above mentioned disease entities. Therefore, all of the disease entities have been lumped into one disease entity: POMT2-related myopathy (MONDO:0700071). Lumping decision approved on 4/13/2021.
Inheritance Pattern: AR
Disease ID:MONDO:0018278
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0018939
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0018277
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0000171
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0013154
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0013160
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0700071
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0013154
Submitter: Genomics England PanelApp
Inheritance Pattern: AR
Disease ID:MONDO:0013154
Submitter: G2P
Clinical Genomic Database (CGD)
Manifestation: Cardiovascular; Musculoskeletal; Neurologic; Ophthalmologic
Intervention: Cardiovascular
Rationale: Conditions may involve cardiovascular manifestations (including dilated cardiomyopathy) and surveillance (eg, with echocardiography) may allow early medical management
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to POMT2 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_013382.7. 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.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 9 | 260 | 4 | 273 | ||
| missense | 5 | 25 | 404 | 19 | 2 | 455 |
| nonsense | 22 | 15 | 37 | |||
| start loss | 0 | |||||
| frameshift | 30 | 34 | 2 | 66 | ||
| splice donor/acceptor (+/-2bp) | 10 | 30 | 4 | 44 | ||
| Total | 67 | 104 | 419 | 279 | 6 | 875 |
Highest pathogenic variant AF is 0.00009420083
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_037514.2 | 21 | MANE Select | |
| Ensembl | ENSP00000261534.4 | 21 | MANE Select | |
| Ensembl | ENSP00000508202.1 | 2 | Standard | |
| Ensembl | ENSP00000451730.1 | 3 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| pomt2 | Danio rerio | Structure: post-vent region Quality: kinked abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Other types of O-glycan biosynthesis - Homo sapiens (human)
- Mannose type O-glycan biosynthesis - Homo sapiens (human)
- Post-translational protein modification
- Metabolism of proteins
- O-linked glycosylation
Biological Process
- protein O-linked mannosylation
- ER-associated misfolded protein catabolic process
- positive regulation of protein O-linked glycosylation
Molecular Function
- dolichyl-phosphate-mannose-protein mannosyltransferase activity
- metal ion binding
Cellular Component
- endoplasmic reticulum membrane
- integral component of membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000261534
- Coding exons
- 21
- Length
- 45929
- Individuals with no LoFs
- 125680
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 68
- Defined
- 125748
- p
- 0.000270
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.0763 | 412 | 416 | 0.989 | 0.0000236 | 4818 |
| Missense (PolyPhen) | 121 | 154.13 | 0.78504 | 1830 | ||
| Synonymous | 0.289 | 162 | 167 | 0.972 | 0.00000920 | 1523 |
| Loss of Function | 2.65 | 25 | 43.9 | 0.569 | 0.00000232 | 473 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00019 | 0.00018 | rare |
| Latino/Admixed American | 0.00026 | 0.00026 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00044 | 0.00044 | rare |
| Finnish | 0.00014 | 0.00014 | rare |
| European (Non-Finnish) | 0.00028 | 0.00027 | rare |
| South Asian | 0.00039 | 0.00039 | rare |
| Other | 0.00033 | 0.00033 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Transfers mannosyl residues to the hydroxyl group of serine or threonine residues. Coexpression of both POMT1 and POMT2 is necessary for enzyme activity, expression of either POMT1 or POMT2 alone is insufficient. {ECO:0000269|PubMed:14699049}.;
- Disease
- DISEASE: Muscular dystrophy-dystroglycanopathy congenital with brain and eye anomalies A2 (MDDGA2) [MIM:613150]: An autosomal recessive disorder characterized by congenital muscular dystrophy associated with cobblestone lissencephaly and other brain anomalies, eye malformations, profound mental retardation, and death usually in the first years of life. Included diseases are the more severe Walker-Warburg syndrome and the slightly less severe muscle-eye-brain disease. {ECO:0000269|PubMed:15894594, ECO:0000269|PubMed:16701995, ECO:0000269|PubMed:17878207, ECO:0000269|PubMed:19138766, ECO:0000269|PubMed:22958903}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Muscular dystrophy-dystroglycanopathy congenital with mental retardation B2 (MDDGB2) [MIM:613156]: An autosomal recessive disorder characterized by congenital muscular dystrophy associated with mental retardation and mild structural brain abnormalities. {ECO:0000269|PubMed:17634419, ECO:0000269|PubMed:19299310}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Muscular dystrophy-dystroglycanopathy limb-girdle C2 (MDDGC2) [MIM:613158]: An autosomal recessive muscular dystrophy with onset after ambulation is achieved. MDDGC2 is characterized by increased serum creatine kinase and mild muscle weakness. Muscle biopsy shows dystrophic changes, inflammatory changes, and severely decreased alpha-dystroglycan. Cognition is normal. {ECO:0000269|PubMed:17878207, ECO:0000269|PubMed:17923109}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.190
Intolerance Scores
- LoFtool
- 0.152
- RVIS EVS
- -0.93
- RVIS percentile EVS
- 9.68
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.459
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |