MARK2microtubule affinity regulating kinase 2
Autism Reports / Total Reports
5 / 5Rare Variants / Common Variants
18 / 0Chromosome Band
11q13.1Associated Disorders
-Genetic Category
Rare Single Gene MutationRelevance to Autism
A two-stage analysis of rare de novo and inherited coding variants in 42,607 ASD cases, including 35,130 new cases for the SPARK cohort, in Zhou et al., 2022 identified MARK2 as a gene reaching exome-wide significance (P < 2.5E-06); association of MARK2 with ASD risk was primarily driven by de novo variants. A de novo missense variant in MARK2 was also identified in an ASD proband from the SAGE cohort in Guo et al., 2019.
Molecular Function
This gene encodes a member of the Par-1 family of serine/threonine protein kinases. The protein is an important regulator of cell polarity in epithelial and neuronal cells, and also controls the stability of microtubules through phosphorylation and inactivation of several microtubule-associating proteins. The protein localizes to cell membranes.
External Links
SFARI Genomic Platforms
Reports related to MARK2 (5 Reports)
| # | Type | Title | Author, Year | Autism Report | Associated Disorders |
|---|---|---|---|---|---|
| 1 | Support | Synaptic, transcriptional and chromatin genes disrupted in autism | De Rubeis S , et al. (2014) | Yes | - |
| 2 | Support | The contribution of de novo coding mutations to autism spectrum disorder | Iossifov I et al. (2014) | Yes | - |
| 3 | Support | Genome sequencing identifies multiple deleterious variants in autism patients with more severe phenotypes | Guo H , et al. (2018) | Yes | - |
| 4 | Primary | - | Zhou X et al. (2022) | Yes | - |
| 5 | Support | - | Chen WX et al. (2022) | Yes | - |
Rare Variants (18)
| Status | Allele Change | Residue Change | Variant Type | Inheritance Pattern | Parental Transmission | Family Type | PubMed ID | Author, Year |
|---|---|---|---|---|---|---|---|---|
| c.211C>T | p.Arg71Ter | stop_gained | De novo | - | - | 35982159 | Zhou X et al. (2022) | |
| c.404-2A>C | - | splice_site_variant | De novo | - | - | 35982159 | Zhou X et al. (2022) | |
| c.457C>T | p.Arg153Ter | stop_gained | De novo | - | - | 35982159 | Zhou X et al. (2022) | |
| c.1934+1G>A | - | splice_site_variant | De novo | - | - | 35982159 | Zhou X et al. (2022) | |
| c.1416+8G>C | - | splice_region_variant | De novo | - | - | 35982159 | Zhou X et al. (2022) | |
| c.403G>A | p.Gly135Arg | missense_variant | De novo | - | - | 35982159 | Zhou X et al. (2022) | |
| c.691G>A | p.Val231Met | missense_variant | De novo | - | - | 35982159 | Zhou X et al. (2022) | |
| c.2029G>A | p.Gly677Ser | missense_variant | De novo | - | - | 35982159 | Zhou X et al. (2022) | |
| c.688G>T | p.Glu230Ter | stop_gained | Familial | Maternal | - | 35982159 | Zhou X et al. (2022) | |
| c.1807C>T | p.Arg603Ter | stop_gained | Familial | Paternal | - | 35982159 | Zhou X et al. (2022) | |
| c.500A>C | p.His167Pro | missense_variant | De novo | - | - | 25363760 | De Rubeis S , et al. (2014) | |
| c.1677-1G>C | - | splice_site_variant | Unknown | Not paternal | - | 35982159 | Zhou X et al. (2022) | |
| c.2029G>A | p.Gly677Ser | missense_variant | De novo | - | Unknown | 30504930 | Guo H , et al. (2018) | |
| c.289C>T | p.Leu97%3D | synonymous_variant | De novo | - | Simplex | 25363768 | Iossifov I et al. (2014) | |
| c.699del | p.Trp234GlyfsTer3 | frameshift_variant | De novo | - | Simplex | 35982159 | Zhou X et al. (2022) | |
| c.179del | p.Gly60AlafsTer8 | frameshift_variant | Familial | Paternal | - | 35982159 | Zhou X et al. (2022) | |
| c.1002del | p.Met335TrpfsTer20 | frameshift_variant | De novo | - | Simplex | 35982159 | Zhou X et al. (2022) | |
| c.1426del | p.Leu476SerfsTer31 | frameshift_variant | De novo | - | Simplex | 36320054 | Chen WX et al. (2022) |
Common Variants
No common variants reported.
SFARI Gene score
2
Strong Candidate
Score Delta: Score remained at 2
criteria met
See SFARI Gene'scoring criteriaWe 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.
10/1/2022
2
Increased from to 2
Krishnan Probability Score
Score 0.49389099424661
Ranking 3933/25841 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.
ExAC Score
Score 0.99990085465415
Ranking 679/18225 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
Sanders TADA Score
Score 0.66496167398313
Ranking 964/18665 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).
Zhang D Score
Score 0.46955795700168
Ranking 752/20870 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.