MCM8

minichromosome maintenance 8 homologous recombination repair factor, the group of MCM family

Basic information

Region (hg38): 20:5950651-5998977

Previous symbols: [ "C20orf154" ]

Links

ENSG00000125885 ∙ NCBI:84515 ∙ OMIM:608187 ∙ HGNC:16147 ∙ Uniprot:Q9UJA3 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• premature ovarian failure 10 (Moderate), mode of inheritance: AR
• premature ovarian failure 10 (Strong), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Premature ovarian failure 10	AR	Endocrine	Individuals have been described with manifestations including hypothyroidism and hypergonadotropic hypogonadism, and response to hormonal therapy has been described as being beneficial	Endocrine; Obstetric	25437880; 25873734
Unlike some other forms of Premature ovarian failure, measures to allow fertility through egg preservation may not be helpful

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the MCM8 gene.

• Inborn genetic diseases (34 variants)
• not provided (19 variants)
• Premature ovarian failure 10 (6 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the MCM8 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous				1	2	3
missense			37		8	45
nonsense	1	1	1			3
start loss						0
frameshift	2					2
inframe indel						0
splice donor/acceptor (+/-2bp)	1	2				3
splice region				1	1	2
non coding						0
Total	4	3	38	1	10

Highest pathogenic variant AF is 0.0000657

Variants in MCM8

This is a list of pathogenic ClinVar variants found in the MCM8 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
20-5952004-C-T			Benign (Jul 14, 2020)
20-5952041-G-T		Inborn genetic diseases	Uncertain significance (Aug 17, 2021)
20-5952104-A-C		Premature ovarian failure 10	Uncertain significance (Apr 22, 2019)
20-5952143-C-G		Inborn genetic diseases	Uncertain significance (Apr 07, 2023)
20-5952149-G-A		Premature ovarian failure 10	Uncertain significance (Jan 27, 2022)
20-5952444-C-T		Inborn genetic diseases	Uncertain significance (Jun 21, 2023)
20-5952448-C-T		Inborn genetic diseases	Uncertain significance (Jan 26, 2022)
20-5952450-A-G		Inborn genetic diseases	Uncertain significance (Nov 17, 2022)
20-5952465-T-G		Inborn genetic diseases	Uncertain significance (Nov 12, 2021)
20-5954615-C-T			Likely benign (Apr 20, 2018)
20-5954627-TTTGA-T			Pathogenic (Nov 29, 2016)
20-5954646-G-C			Benign (Dec 31, 2019)
20-5954673-A-G		Inborn genetic diseases	Uncertain significance (Jul 12, 2022)
20-5954679-T-G			Benign (May 04, 2018)
20-5955109-TAGAA-T			Pathogenic (Jun 27, 2022)
20-5955177-A-G		Inborn genetic diseases	Uncertain significance (Dec 28, 2023)
20-5955179-A-G		MCM8-related disorder	Benign (Jul 02, 2019)
20-5955186-A-G			Benign (Dec 31, 2019)
20-5955211-C-G		Premature ovarian failure 10	Pathogenic (Dec 01, 2014)
20-5955229-G-A			Benign (Dec 31, 2019)
20-5955247-A-C		Azoospermia	Pathogenic (Dec 20, 2021)
20-5957171-C-G		Inborn genetic diseases	Uncertain significance (May 30, 2023)
20-5957187-A-G			Benign (Dec 31, 2019)
20-5957193-G-C		Inborn genetic diseases	Uncertain significance (Oct 05, 2023)
20-5957214-C-A		Inborn genetic diseases	Uncertain significance (Mar 16, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
MCM8	protein_coding	protein_coding	ENST00000378896	18	44555

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.05e-16	0.644	125606	0	142	125748	0.000565

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.357	426	447	0.953	0.0000228	5483
Missense in Polyphen		149	179.28	0.83109		2176
Synonymous	0.295	148	153	0.970	0.00000758	1607
Loss of Function	1.85	32	45.5	0.704	0.00000256	550

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00113	0.00113
Ashkenazi Jewish	0.000497	0.000298
East Asian	0.000384	0.000381
Finnish	0.000325	0.000323
European (Non-Finnish)	0.000628	0.000624
Middle Eastern	0.000384	0.000381
South Asian	0.000636	0.000621
Other	0.000326	0.000326

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Component of the MCM8-MCM9 complex, a complex involved in the repair of double-stranded DNA breaks (DBSs) and DNA interstrand cross-links (ICLs) by homologous recombination (HR) (PubMed:23401855). Required for DNA resection by the MRE11-RAD50- NBN/NBS1 (MRN) complex by recruiting the MRN complex to the repair site and by promoting the complex nuclease activity (PubMed:26215093). Probably by regulating the localization of the MNR complex, indirectly regulates the recruitment of downstream effector RAD51 to DNA damage sites including DBSs and ICLs (PubMed:23401855). The MCM8-MCM9 complex is dispensable for DNA replication and S phase progression (PubMed:23401855). However, may play a non-essential for DNA replication: may be involved in the activation of the prereplicative complex (pre-RC) during G(1) phase by recruiting CDC6 to the origin recognition complex (ORC) (PubMed:15684404). Probably by regulating HR, plays a key role during gametogenesis (By similarity). Stabilizes MCM9 protein (PubMed:23401855, PubMed:26215093). {ECO:0000250|UniProtKB:Q9CWV1, ECO:0000269|PubMed:15684404, ECO:0000269|PubMed:23401855, ECO:0000269|PubMed:26215093}.
• Disease: DISEASE: Premature ovarian failure 10 (POF10) [MIM:612885]: An ovarian disorder defined as the cessation of ovarian function under the age of 40 years. It is characterized by oligomenorrhea or amenorrhea, in the presence of elevated levels of serum gonadotropins and low estradiol. {ECO:0000269|PubMed:25437880}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Cell Cycle;Activation of ATR in response to replication stress;G2/M Checkpoints;Cell Cycle Checkpoints;Activation of the pre-replicative complex;E2F mediated regulation of DNA replication;Unwinding of DNA;Mitotic G1-G1/S phases;Orc1 removal from chromatin;DNA Replication;Switching of origins to a post-replicative state;DNA strand elongation;Synthesis of DNA;S Phase;G1/S Transition;E2F-enabled inhibition of pre-replication complex formation;CDC6 association with the ORC:origin complex;CDT1 association with the CDC6:ORC:origin complex;Assembly of the pre-replicative complex;DNA Replication Pre-Initiation;M/G1 Transition;Cell Cycle;Cell Cycle, Mitotic (Consensus)

Recessive Scores

• pRec: 0.198

Intolerance Scores

• loftool: 0.997
• rvis_EVS: 1.41
• rvis_percentile_EVS: 94.79

Haploinsufficiency Scores

• pHI: 0.246
• hipred: Y
• hipred_score: 0.644
• ghis: 0.546

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: K
• gene_indispensability_pred: E
• gene_indispensability_score: 0.986

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	High
Cancer	Medium	Medium	High

Mouse Genome Informatics

• Gene name: Mcm8
• Phenotype: endocrine/exocrine gland phenotype; homeostasis/metabolism phenotype; cellular phenotype; neoplasm; reproductive system phenotype

Gene ontology

• Biological process: G1/S transition of mitotic cell cycle;double-strand break repair via homologous recombination;DNA replication;cellular response to DNA damage stimulus;female gamete generation;recombinational interstrand cross-link repair;male gamete generation;protein stabilization;protein localization to chromatin
• Cellular component: nucleus;nucleoplasm;chromosome;MCM8-MCM9 complex
• Molecular function: DNA binding;chromatin binding;helicase activity;protein binding;ATP binding;enzyme binding;MutLbeta complex binding;MutSalpha complex binding;MutSbeta complex binding