MOCS2
protein-codingmolybdenum cofactor synthesis 2
Gene summary
Eukaryotic molybdoenzymes use a unique molybdenum cofactor (MoCo) consisting of a pterin, termed molybdopterin, and the catalytically active metal molybdenum. MoCo is synthesized from precursor Z by the heterodimeric enzyme molybdopterin synthase. The large and small subunits of molybdopterin synthase are both encoded from this gene by overlapping open reading frames. The proteins were initially thought to be encoded from a bicistronic transcript. They are now thought to be encoded from monocistronic transcripts. Alternatively spliced transcripts have been found for this locus that encode the large and small subunits. [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 ~14.4 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0009644
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0009644
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0009644
Submitter: Natera
Inheritance Pattern: AR
Disease ID:MONDO:0009644
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0009644
Submitter: ClinGen
*MOCS2* was first reported in relation to autosomal recessive molybdenum cofactor deficiency type B in 1999 (Reiss et al., PMID: 10053004). Molybdenum cofactor deficiency type B is characterized by refractory neonatal seizures, dysmorphic features, ocular lens dislocation, and a characteristic urinary profile indicative of an underlying biochemical dysfunction (PMID:33017596). The underlying mechanism is a failure to synthesize molybdenum cofactor, leading to loss of function of the enzymes sulfite oxidase, xanthine oxidase, and aldehyde oxidase (PMID:33017596). Eight variants (two missense, one nonsense, three frameshift, one splice-acceptor site, one start-loss) that have been reported in seven probands in three publications (PMID: 10053004, 25709896, 16021469) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is known to be biallelic loss-of-function. The *MOCS2* gene encodes both the large and small subunits of the homotetrameric molybdopterin synthase enzyme. Biallelic loss of function of either subunit is sufficient to cause disease. This gene-disease association is also supported by expression studies, in vitro functional assays, and an animal model (PMID: 27138983, 33017596). Expression of this gene is enriched in the liver, kidney, and brain. Homozygous knock-out of the homologous gene in mice leads to the combined loss of sulfite oxidase, xanthine oxidase, and aldehyde oxidase activities. Further, these mice fail to thrive and have a significantly reduced lifespan. In summary, *MOCS2* is definitively associated with autosomal recessive molybdenum cofactor deficiency type B. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time without the emergence of contradictory evidence. This classification was approved by the ClinGen General Inborn Errors of Metabolism GCEP on 12/9/2022 (SOP Version 9).
Inheritance Pattern: AR
Disease ID:MONDO:0009644
Submitter: Labcorp Genetics (formerly Invitae)
Clinical Genomic Database (CGD)
Manifestation: Biochemical; Neurologic
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 MOCS2 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_004531.5. 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 | 5 | 51 | 56 | |||
| missense | 1 | 2 | 69 | 14 | 2 | 88 |
| nonsense | 3 | 1 | 2 | 6 | ||
| start loss | 2 | 1 | 3 | |||
| frameshift | 15 | 6 | 2 | 23 | ||
| splice donor/acceptor (+/-2bp) | 4 | 4 | ||||
| Total | 21 | 13 | 78 | 66 | 2 | 180 |
Highest pathogenic variant AF is 0.00010658232
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_004522.1 | 5 | MANE Select | |
| Ensembl | ENSP00000380157.3 | 5 | MANE Select | |
| RefSeq | NP_789776.1 | 3 | MANE Plus Clinical | |
| Ensembl | ENSP00000355160.4 | 3 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Folate biosynthesis - Homo sapiens (human)
- Sulfur relay system - Homo sapiens (human)
- Metabolism
- Molybdenum cofactor biosynthesis
- Metabolism of water-soluble vitamins and cofactors
Biological Process
- Mo-molybdopterin cofactor biosynthetic process
- molybdopterin cofactor biosynthetic process
Molecular Function
- molybdopterin synthase activity
Cellular Component
- nucleus
- cytosol
- nuclear speck
- molybdopterin synthase complex
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000396954
- Coding exons
- 5
- Length
- 14385
- Individuals with no LoFs
- 125712
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 34
- Defined
- 125746
- p
- 0.000135
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -0.0788 | 101 | 98.8 | 1.02 | 0.00000482 | 1229 |
| Missense (PolyPhen) | 21 | 26.575 | 0.79021 | 322 | ||
| Synonymous | 0.710 | 34 | 39.7 | 0.857 | 0.00000241 | 340 |
| Loss of Function | 0.793 | 6 | 8.49 | 0.707 | 3.54e-7 | 120 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000062 | 0.000062 | rare |
| Latino/Admixed American | 0.000029 | 0.000029 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.000054 | 0.000054 | rare |
| Finnish | 0.00084 | 0.00083 | rare |
| European (Non-Finnish) | 0.000071 | 0.000070 | rare |
| South Asian | 0.00016 | 0.00016 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Catalytic subunit of the molybdopterin synthase complex, a complex that catalyzes the conversion of precursor Z into molybdopterin. Acts by mediating the incorporation of 2 sulfur atoms from thiocarboxylated MOCS2A into precursor Z to generate a dithiolene group. {ECO:0000255|HAMAP-Rule:MF_03052, ECO:0000269|PubMed:12732628, ECO:0000269|PubMed:15073332}.;
Recessive Scores
- pRec
- 0.175
Intolerance Scores
- LoFtool
- 0.860
- RVIS EVS
- 0.53
- RVIS percentile EVS
- 80.73
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.141
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |