MCM2

Chr 3AD

minichromosome maintenance complex component 2

Also known as: BM28, CCNL1, CDCL1, D3S3194, DFNA70, MITOTIN, cdc19

NCBI Gene: 4171 ENSG00000073111 UniProt: P33993 OMIM: 116945

The MCM2 protein is a core component of the MCM2-7 replicative helicase complex that is essential for DNA replication initiation and elongation in eukaryotic cells. Biallelic MCM2 mutations cause primary microcephaly and growth retardation, inherited in an autosomal recessive pattern. The gene is highly constrained against loss-of-function variants in the general population, reflecting its critical role in fundamental cellular processes.

OMIM ResearchSummary from RefSeq, UniProt

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]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

?Deafness, autosomal dominant 70MIM #616968

Clinical highlights

Gene–disease validity (ClinGen)

Limited · nonsyndromic genetic hearing loss · AD · ClinGen 2020

not for standalone diagnostic reporting

Active trials

131

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.58

LOEUF

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.58LOEUF

pLI 0.000

Z-score 3.61

OE 0.38 (0.25–0.58)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.68Z-score

OE missense 0.81 (0.75–0.87)

490 obs / 606.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.38 (0.25–0.58)

0≤0.351.4

Missense OE?0.81 (0.75–0.87)

0≤0.61.4

Synonymous OE?1.11

0≤1.21.6

LoF obs/exp: 15 / 39.5Missense obs/exp: 490 / 606.2Syn Z: -1.36

Background carrier burden — how many people carry a rare variant somewhere in MCM2?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 46

1,152 rare PASS variants

Rare truncating (LoF)

1 in 1,900

124 rare PASS variants

Rare synonymous (reference)

1 in 71

521 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for MCM2. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 55	1 in 2,200
South Asian	~43k	1 in 35	1 in 1,300
Remaining (unassigned)	~30k	1 in 40	1 in 1,900
European (Finnish)	~27k	1 in 110	1 in 1,700
Admixed American	~22k	1 in 52	1 in 2,500
African / African American	~21k	1 in 51	1 in 1,000
East Asian	~20k	1 in 42	1 in 2,000
Ashkenazi Jewish	~13k	1 in 290	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 37	≈ 1 in 1,400

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 16 coding exons well covered in gnomAD exomes and genomes.? see exons ↓