Human Gene Module / Chromosome 14 / CCDC88C

CCDC88CCoiled-coil domain containing 88C

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
9 / 9
Rare Variants / Common Variants
13 / 0
Aliases
CCDC88C, DAPLE,  HKRP2,  KIAA1509,  SCA40
Associated Syndromes
-
Chromosome Band
14q32.11-q32.12
Associated Disorders
-
Relevance to Autism

Two de novo missense variants in the CCDC88C gene were identified in simplex ASD probands, with no de novo events in this gene observed in 1,786 unaffected siblings from the Simons Simplex Collection (P=0.07) (Iossifov et al., 2014; Krumm et al., 2015).

Molecular Function

This gene encodes a ubiquitously expressed coiled-coil domain-containing protein that interacts with the dishevelled protein and is a negative regulator of the canonical Wnt signaling pathway, acting downstream of DVL to inhibit CTNNB1/Beta-catenin stabilization. Mutations in this gene cause autosomal recessive, primary non-syndromic congenital hydrocephalus; a condition characterized by excessive accumulation of cerebrospinal fluid in the ventricles of the brain.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to CCDC88C (9 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
2 Primary Excess of rare, inherited truncating mutations in autism Krumm N , et al. (2015) Yes -
3 Support Genome-wide characteristics of de novo mutations in autism Yuen RK et al. (2016) Yes -
4 Support De novo genic mutations among a Chinese autism spectrum disorder cohort Wang T , et al. (2016) Yes -
5 Support Integrative Analyses of De Novo Mutations Provide Deeper Biological Insights into Autism Spectrum Disorder Takata A , et al. (2018) Yes -
6 Support Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model Guo H , et al. (2018) Yes -
7 Support - Woodbury-Smith M et al. (2022) Yes -
8 Support - Zhou X et al. (2022) Yes -
9 Support - Cirnigliaro M et al. (2023) Yes -
Rare Variants   (13)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.2090G>A p.Arg697His missense_variant De novo - Multiplex 35982159 Zhou X et al. (2022)
c.466G>A p.Val156Met missense_variant Familial Maternal - 27824329 Wang T , et al. (2016)
c.935G>A p.Arg312Gln missense_variant Familial Maternal - 27824329 Wang T , et al. (2016)
c.5636G>A p.Arg1879Gln missense_variant De novo - Simplex 27525107 Yuen RK et al. (2016)
c.4921C>G p.Leu1641Val missense_variant De novo - Simplex 25961944 Krumm N , et al. (2015)
c.3748G>A p.Glu1250Lys missense_variant De novo - Simplex 29346770 Takata A , et al. (2018)
c.5222A>G p.Glu1741Gly missense_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.5510G>A p.Gly1837Asp missense_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.567G>A p.Ser189%3D synonymous_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.3336G>C p.Gln1112His missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.760G>A p.Val254Ile missense_variant Familial Maternal Simplex 30564305 Guo H , et al. (2018)
c.3565A>G p.Ile1189Val missense_variant Familial Maternal Simplex 30564305 Guo H , et al. (2018)
c.3700C>T p.Arg1234Ter stop_gained Familial Paternal Multiplex 37506195 Cirnigliaro M et al. (2023)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

Two de novo missense variants in the gene were identified in simplex ASD probands, with no de novo events in this gene observed in 1,786 unaffected siblings from the Simons Simplex Collection (P=0.07) (Iossifov et al., 2014; Krumm et al., 2015).

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

Two de novo missense variants in the gene were identified in simplex ASD probands, with no de novo events in this gene observed in 1,786 unaffected siblings from the Simons Simplex Collection (P=0.07) (Iossifov et al., 2014; Krumm et al., 2015).

10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

Two de novo missense variants in the gene were identified in simplex ASD probands, with no de novo events in this gene observed in 1,786 unaffected siblings from the Simons Simplex Collection (P=0.07) (Iossifov et al., 2014; Krumm et al., 2015).

Reports Added
[New Scoring Scheme]
1/1/2019
4
icon
4

Decreased from 4 to 4

Description

Two de novo missense variants in the gene were identified in simplex ASD probands, with no de novo events in this gene observed in 1,786 unaffected siblings from the Simons Simplex Collection (P=0.07) (Iossifov et al., 2014; Krumm et al., 2015).

Reports Added
[Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model.2018]
10/1/2016
4
icon
4

Decreased from 4 to 4

Description

Two de novo missense variants in the gene were identified in simplex ASD probands, with no de novo events in this gene observed in 1,786 unaffected siblings from the Simons Simplex Collection (P=0.07) (Iossifov et al., 2014; Krumm et al., 2015).

Reports Added
[De novo genic mutations among a Chinese autism spectrum disorder cohort.2016]
7/1/2016
4
icon
4

Decreased from 4 to 4

Description

Two de novo missense variants in the gene were identified in simplex ASD probands, with no de novo events in this gene observed in 1,786 unaffected siblings from the Simons Simplex Collection (P=0.07) (Iossifov et al., 2014; Krumm et al., 2015).

Reports Added
[Genome-wide characteristics of de novo mutations in autism2016]
7/1/2015
icon
4

Increased from to 4

Description

Two de novo missense variants in the gene were identified in simplex ASD probands, with no de novo events in this gene observed in 1,786 unaffected siblings from the Simons Simplex Collection (P=0.07) (Iossifov et al., 2014; Krumm et al., 2015).

Krishnan Probability Score

Score 0.4154073598495

Ranking 21491/25841 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 2.1732276999498E-6

Ranking 14784/18225 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 0.94728903604439

Ranking 17215/18665 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 0.14740964160898

Ranking 5241/20870 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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