MCM2
protein-codingminichromosome maintenance complex component 2, the group of MCM family|minichromosome maintenance 2-7 complex
Gene summary
The protein encoded by this gene is one of the highly conserved mini-chromosome maintenance proteins (MCM) that are involved in the initiation of eukaryotic genome replication. The hexameric protein complex formed by MCM proteins is a key component of the pre-replication complex (pre_RC) and may be involved in the formation of replication forks and in the recruitment of other DNA replication related proteins. This protein forms a complex with MCM4, 6, and 7, and has been shown to regulate the helicase activity of the complex. This protein is phosphorylated, and thus regulated by, protein kinases CDC2 and CDC7. Multiple alternatively spliced transcript variants have been found, but the full-length nature of some variants has not been defined. [provided by RefSeq, Oct 2012]
- CCNL1
- CDCL1
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~24.2 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0019497
Submitter: ClinGen
MCM2 was reported in relation to autosomal dominant nonsyndromic genetic deafness in 2015 (Gao et al., PMID: 26196677). At least 1 unique variant (missense) has been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Variants in this gene have been reported in at least 1 proband in 1 publication (PMID: 26196677). Variants in this gene segregated with disease in 8 additional family members. This gene-disease association is supported by an expression study and in vitro functional assay. 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 ClinGen Hearing Loss Working Group on 2/6/2020.
Inheritance Pattern: AD
Disease ID:MONDO:0014853
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0014853
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0019587
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0014853
Submitter: Ambry Genetics
Clinical Genomic Database (CGD)
Manifestation: Audiologic/Otolaryngologic
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 MCM2 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_004526.4. 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 | 2 | 84 | 6 | 92 | ||
| missense | 1 | 218 | 30 | 4 | 253 | |
| nonsense | 1 | 1 | ||||
| start loss | 1 | 1 | ||||
| frameshift | 1 | 1 | ||||
| splice donor/acceptor (+/-2bp) | 1 | 1 | ||||
| Total | 0 | 2 | 223 | 114 | 10 | 349 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_004517.2 | 16 | MANE Select | |
| Ensembl | ENSP00000265056.7 | 16 | MANE Select | |
| Ensembl | ENSP00000418930.1 | 2 | Standard | |
| Ensembl | ENSP00000420007.1 | 4 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| mcm2 | Danio rerio | Structure: pharyngeal arch 3-7 Quality: aplastic abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Cell cycle - Homo sapiens (human)
- DNA replication - Homo sapiens (human)
- Cell Cycle
- G1 to S cell cycle control
- DNA Replication
Biological Process
- G1/S transition of mitotic cell cycle
- DNA replication
- DNA unwinding involved in DNA replication
- DNA replication initiation
- nucleosome assembly
Molecular Function
- DNA binding
- DNA replication origin binding
- helicase activity
- protein binding
- ATP binding
Cellular Component
- nuclear chromosome, telomeric region
- chromatin
- nucleus
- nucleoplasm
- nuclear origin of replication recognition complex
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000265056
- Coding exons
- 16
- Length
- 24211
- Individuals with no LoFs
- 125705
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 43
- Defined
- 125748
- p
- 0.000171
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.68 | 490 | 606 | 0.808 | 0.0000418 | 5984 |
| Missense (PolyPhen) | 151 | 225.96 | 0.66827 | 2235 | ||
| Synonymous | -1.36 | 268 | 241 | 1.11 | 0.0000169 | 1786 |
| Loss of Function | 3.61 | 15 | 39.5 | 0.380 | 0.00000213 | 440 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00018 | 0.00018 | rare |
| Latino/Admixed American | 0.00020 | 0.00017 | rare |
| Ashkenazi Jewish | 0.000099 | 0.000099 | rare |
| East Asian | 0.00033 | 0.00033 | rare |
| Finnish | 0.00018 | 0.00018 | rare |
| European (Non-Finnish) | 0.00016 | 0.00016 | rare |
| South Asian | 0.000065 | 0.000065 | rare |
| Other | 0.00049 | 0.00049 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Acts as component of the MCM2-7 complex (MCM complex) which is the putative replicative helicase essential for 'once per cell cycle' DNA replication initiation and elongation in eukaryotic cells. The active ATPase sites in the MCM2-7 ring are formed through the interaction surfaces of two neighboring subunits such that a critical structure of a conserved arginine finger motif is provided in trans relative to the ATP-binding site of the Walker A box of the adjacent subunit. The six ATPase active sites, however, are likely to contribute differentially to the complex helicase activity. Required for the entry in S phase and for cell division. Plays a role in terminally differentiated hair cells development of the cochlea and induces cells apoptosis. {ECO:0000269|PubMed:26196677, ECO:0000269|PubMed:8175912}.;
- Disease
- DISEASE: Deafness, autosomal dominant, 70 (DFNA70) [MIM:616968]: A form of non-syndromic sensorineural hearing loss. Sensorineural deafness results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information. DFNA70 is characterized by slowly progressive, postlingual hearing impairment. {ECO:0000269|PubMed:26196677}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.129
Intolerance Scores
- LoFtool
- 0.429
- RVIS EVS
- -0.95
- RVIS percentile EVS
- 9.38
Essentials
- Essential (CRISPR)
- E
- Essential (CRISPR2)
- E
- Essential (gene trap)
- E
- 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 |