Human Gene Module / Chromosome 2 / MCM6

MCM6minichromosome maintenance complex component 6

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
4 / 4
Rare Variants / Common Variants
9 / 0
Aliases
MCM6, MCG40308,  Mis5,  P105MCM
Associated Syndromes
-
Chromosome Band
2q21.3
Associated Disorders
-
Relevance to Autism

De novo missense variants that were predicted in silico to be damaging were observed in the MCM6 gene in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014) and an ASD proband from a cohort of 262 Japanese trios (Takata et al., 2018). TADA-Denovo analysis using a combined dataset of previously published cohorts from the Simons Simplex Collection and the Autism Sequencing Consortium, as well as the Japanese ASD cohort from Takata et al., 2018, identified MCM6 as a gene significantly enriched in damaging de novo mutations in ASD cases (pBH < 0.05).

Molecular Function

The protein encoded by this gene is one of the highly conserved mini-chromosome maintenance proteins (MCM) that are essential for the initiation of eukaryotic genome replication. The hexameric protein complex formed by the 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. The MCM complex consisting of this protein and MCM2, 4 and 7 proteins possesses DNA helicase activity, and may act as a DNA unwinding enzyme. The phosphorylation of the complex by CDC2 kinase reduces the helicase activity, suggesting a role in the regulation of DNA replication.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
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SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to MCM6 (4 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
2 Recent Recommendation Integrative Analyses of De Novo Mutations Provide Deeper Biological Insights into Autism Spectrum Disorder Takata A , et al. (2018) Yes -
3 Support - Zhou X et al. (2022) Yes -
4 Recent Recommendation - Smits DJ et al. (2023) Yes ID, epilepsy/seizures
Rare Variants   (9)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.445C>T p.Pro149Ser missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.2054-1G>A - splice_site_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.473G>A p.Cys158Tyr missense_variant De novo - - 37198333 Smits DJ et al. (2023)
c.605A>G p.Asp202Gly missense_variant De novo - - 37198333 Smits DJ et al. (2023)
c.715G>A p.Gly239Ser missense_variant De novo - - 37198333 Smits DJ et al. (2023)
c.445C>T p.Pro149Ser missense_variant De novo - Simplex 29346770 Takata A , et al. (2018)
c.1230G>A p.Glu410%3D synonymous_variant De novo - Multiplex 35982159 Zhou X et al. (2022)
c.2097C>T p.Tyr699%3D synonymous_variant De novo - Multiplex 35982159 Zhou X et al. (2022)
c.1693C>T p.Arg565Cys missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

De novo missense variants that were predicted in silico to be damaging were observed in the MCM6 gene in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014) and an ASD proband from a cohort of 262 Japanese trios (Takata et al., 2018). TADA-Denovo analysis using a combined dataset of previously published cohorts from the Simons Simplex Collection and the Autism Sequencing Consortium, as well as the Japanese ASD cohort from Takata et al., 2018, identified MCM6 as a gene significantly enriched in damaging de novo mutations in ASD cases (pBH < 0.05).

Score Delta: Score remained at 2

criteria met
See SFARI Gene'scoring criteria
2

Strong Candidate

See all Category 2 Genes

We considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.

4/1/2022
3
icon
2

Decreased from 3 to 2

Description

De novo missense variants that were predicted in silico to be damaging were observed in the MCM6 gene in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014) and an ASD proband from a cohort of 262 Japanese trios (Takata et al., 2018). TADA-Denovo analysis using a combined dataset of previously published cohorts from the Simons Simplex Collection and the Autism Sequencing Consortium, as well as the Japanese ASD cohort from Takata et al., 2018, identified MCM6 as a gene significantly enriched in damaging de novo mutations in ASD cases (pBH < 0.05).

10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

De novo missense variants that were predicted in silico to be damaging were observed in the MCM6 gene in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014) and an ASD proband from a cohort of 262 Japanese trios (Takata et al., 2018). TADA-Denovo analysis using a combined dataset of previously published cohorts from the Simons Simplex Collection and the Autism Sequencing Consortium, as well as the Japanese ASD cohort from Takata et al., 2018, identified MCM6 as a gene significantly enriched in damaging de novo mutations in ASD cases (pBH < 0.05).

Reports Added
[New Scoring Scheme]
7/1/2018
icon
4

Increased from to 4

Description

De novo missense variants that were predicted in silico to be damaging were observed in the MCM6 gene in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014) and an ASD proband from a cohort of 262 Japanese trios (Takata et al., 2018). TADA-Denovo analysis using a combined dataset of previously published cohorts from the Simons Simplex Collection and the Autism Sequencing Consortium, as well as the Japanese ASD cohort from Takata et al., 2018, identified MCM6 as a gene significantly enriched in damaging de novo mutations in ASD cases (pBH < 0.05).

Krishnan Probability Score

Score 0.49097428996297

Ranking 5870/25841 scored genes


[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
Original Source
ExAC Score

Score 0.99848201951436

Ranking 1188/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
Original Source
Sanders TADA Score

Score 0.76300986948696

Ranking 1692/18665 scored genes


[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Original Source
Zhang D Score

Score 0.18408395281498

Ranking 4535/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
Original Source
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