Human Gene Module / Chromosome 19 / CIC

CICcapicua transcriptional repressor

SFARI Gene Score
1
High Confidence Criteria 1.1
Autism Reports / Total Reports
11 / 16
Rare Variants / Common Variants
28 / 0
EAGLE Score
18.7
Strong Learn More
Aliases
-
Associated Syndromes
-
Chromosome Band
19q13.2
Associated Disorders
ASD, EPS
Genetic Category
Rare Single Gene Mutation, Syndromic, Functional
Relevance to Autism

A de novo loss-of-function (LoF) variant in the CIC gene was first identified in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014). A second de novo LoF variant in this gene was identified by whole genome sequencing in an ASD proband from a simplex family as part of the MSSNG initiative in Yuen et al., 2017. Based on the discovery of two de novo LoF variants in ASD cases, a probability of LoF intolerance rate (pLI) > 0.9, and a higher-than expected mutation rate (a false discovery rate < 15%), CIC was determined to be an ASD candidate gene in Yuen et al., 2017. Lu et al., 2017 demonstrated that deletion of Cic from the developing mouse forebrain resulted in hyperactivity, impaired learning and memory, and abnormal maturation and maintainence of upper-layer cortical neurons, whereas deletion of Cic from the hypothalamus and medial amygdala resulted in abnormal social behavior in mice. Lu et al., 2017 also identified loss-of-function variants in CIC in five patients with similar clinical features, including developmental delay/intellectual disability, ASD/autistic features, and seizures.

Molecular Function

The protein encoded by this gene is an ortholog of the Drosophila melanogaster capicua gene, and is a member of the high mobility group (HMG)-box superfamily of transcriptional repressors. It may play a role in development of the central nervous system.

SFARI Genomic Platforms
Reports related to CIC (16 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support A de novo paradigm for mental retardation Vissers LE , et al. (2010) No -
2 Primary The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
3 Recent Recommendation Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder C Yuen RK et al. (2017) Yes -
4 Recent Recommendation Disruption of the ATXN1-CIC complex causes a spectrum of neurobehavioral phenotypes in mice and humans Lu HC , et al. (2017) No ASDor autistic features, epilepsy/seizures
5 Support Genome sequencing identifies multiple deleterious variants in autism patients with more severe phenotypes Guo H , et al. (2018) Yes -
6 Support Utility of clinical exome sequencing in a complex Emirati pediatric cohort Mahfouz NA et al. (2020) Yes -
7 Support - Wilfert AB et al. (2021) Yes -
8 Support - Sharma S et al. (2022) No ASD, ID, epilepsy/seizures
9 Support - Zhou X et al. (2022) Yes -
10 Support - Chan AJS et al. (2022) Yes -
11 Support - Wang J et al. (2023) Yes -
12 Support - Sheth F et al. (2023) Yes DD, ID
13 Support - Karthika Ajit Valaparambil et al. () No -
14 Support - Omri Bar et al. (2024) Yes Learning disability
15 Support - Axel Schmidt et al. (2024) No -
16 Support - Suhua Chang et al. () Yes -
Rare Variants   (28)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.7187-8A>G - splice_region_variant De novo - - 35982159 Zhou X et al. (2022)
c.673C>T p.Arg225Cys stop_gained De novo - - 35165976 Sharma S et al. (2022)
c.1057C>T p.Arg353Ter stop_gained De novo - Simplex 28288114 Lu HC , et al. (2017)
c.673C>T p.Arg225Cys stop_gained Familial - Simplex 28263302 C Yuen RK et al. (2017)
c.1582C>T p.Arg528Ter stop_gained De novo - Simplex 28263302 C Yuen RK et al. (2017)
c.820C>T p.Arg274Ter stop_gained De novo - Simplex 25363768 Iossifov I et al. (2014)
c.4265C>T p.Ser1422Leu missense_variant De novo - - 39039281 Axel Schmidt et al. (2024)
c.1852G>A p.Ala618Thr missense_variant Unknown - Simplex 37543562 Sheth F et al. (2023)
c.3547C>T p.Arg1183Ter stop_gained Familial - Simplex 34312540 Wilfert AB et al. (2021)
c.7480C>T p.Gln2494Ter stop_gained Familial - Simplex 34312540 Wilfert AB et al. (2021)
c.1015G>C p.Glu339Gln missense_variant De novo - Multiplex 35982159 Zhou X et al. (2022)
c.6746A>C p.Lys2249Thr missense_variant De novo - Simplex 39126614 Suhua Chang et al. ()
c.457C>T p.Pro153Ser missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.2864C>T p.Pro955Leu stop_gained Familial Paternal Simplex 28288114 Lu HC , et al. (2017)
c.1100dup p.Pro368AlafsTer16 frameshift_variant De novo - - 35165976 Sharma S et al. (2022)
c.1474C>T p.Arg492Trp missense_variant De novo - Simplex 21076407 Vissers LE , et al. (2010)
c.683G>A p.Arg228Gln missense_variant Unknown Not maternal - 35165976 Sharma S et al. (2022)
c.1927G>C p.Gly643Arg missense_variant Unknown - Multiplex 32382396 Mahfouz NA et al. (2020)
c.65del p.Pro22GlnfsTer8 frameshift_variant Familial Paternal - 36309498 Chan AJS et al. (2022)
c.1246dup p.Leu416ProfsTer138 frameshift_variant De novo - Simplex 37393044 Wang J et al. (2023)
c.3439_3440del p.Trp1147ValfsTer76 frameshift_variant De novo - - 35165976 Sharma S et al. (2022)
c.4427C>T p.Thr1476Ile missense_variant Unknown - - 37943464 Karthika Ajit Valaparambil et al. ()
c.2323C>T p.Arg775Cys missense_variant Familial Paternal Simplex 38256266 Omri Bar et al. (2024)
c.774_783del p.Pro259ValfsTer88 frameshift_variant De novo - Simplex 30504930 Guo H , et al. (2018)
c.4143del p.Asp1382ThrfsTer26 frameshift_variant Familial - Simplex 34312540 Wilfert AB et al. (2021)
c.6796del p.Glu2266SerfsTer58 frameshift_variant Familial - Simplex 34312540 Wilfert AB et al. (2021)
c.2571_2578delinsC p.Thr859AlafsTer63 frameshift_variant De novo - Simplex 28288114 Lu HC , et al. (2017)
c.4528_4535dup p.Glu1513ArgfsTer127 frameshift_variant De novo - Multiplex (presumed germline mosaicism) 28288114 Lu HC , et al. (2017)
Common Variants  

No common variants reported.

SFARI Gene score
1

High Confidence

Score Delta: Score remained at 1

1

High Confidence

See all Category 1 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.

4/1/2020
1
icon
1

Score remained at 1

Description

A de novo loss-of-function (LoF) variant in the CIC gene was first identified in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014). A second de novo LoF variant in this gene was identified by whole genome sequencing in an ASD proband from a simplex family as part of the MSSNG initiative in Yuen et al., 2017. Based on the discovery of two de novo LoF variants in ASD cases, a probability of LoF intolerance rate (pLI) > 0.9, and a higher-than expected mutation rate (a false discovery rate < 15%), CIC was determined to be an ASD candidate gene in Yuen et al., 2017. Lu et al., 2017 demonstrated that deletion of Cic from the developing mouse forebrain resulted in hyperactivity, impaired learning and memory, and abnormal maturation and maintainence of upper-layer cortical neurons, whereas deletion of Cic from the hypothalamus and medial amygdala resulted in abnormal social behavior in mice. Lu et al., 2017 also identified loss-of-function variants in CIC in five patients with similar clinical features, including developmental delay/intellectual disability, ASD/autistic features, and seizures.

10/1/2019
2S
icon
1

Decreased from 2S to 1

New Scoring Scheme
Description

A de novo loss-of-function (LoF) variant in the CIC gene was first identified in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014). A second de novo LoF variant in this gene was identified by whole genome sequencing in an ASD proband from a simplex family as part of the MSSNG initiative in Yuen et al., 2017. Based on the discovery of two de novo LoF variants in ASD cases, a probability of LoF intolerance rate (pLI) > 0.9, and a higher-than expected mutation rate (a false discovery rate < 15%), CIC was determined to be an ASD candidate gene in Yuen et al., 2017. Lu et al., 2017 demonstrated that deletion of Cic from the developing mouse forebrain resulted in hyperactivity, impaired learning and memory, and abnormal maturation and maintainence of upper-layer cortical neurons, whereas deletion of Cic from the hypothalamus and medial amygdala resulted in abnormal social behavior in mice. Lu et al., 2017 also identified loss-of-function variants in CIC in five patients with similar clinical features, including developmental delay/intellectual disability, ASD/autistic features, and seizures.

Reports Added
[New Scoring Scheme]
10/1/2018
2S
icon
2S

Decreased from 2S to 2S

Description

A de novo loss-of-function (LoF) variant in the CIC gene was first identified in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014). A second de novo LoF variant in this gene was identified by whole genome sequencing in an ASD proband from a simplex family as part of the MSSNG initiative in Yuen et al., 2017. Based on the discovery of two de novo LoF variants in ASD cases, a probability of LoF intolerance rate (pLI) > 0.9, and a higher-than expected mutation rate (a false discovery rate < 15%), CIC was determined to be an ASD candidate gene in Yuen et al., 2017. Lu et al., 2017 demonstrated that deletion of Cic from the developing mouse forebrain resulted in hyperactivity, impaired learning and memory, and abnormal maturation and maintainence of upper-layer cortical neurons, whereas deletion of Cic from the hypothalamus and medial amygdala resulted in abnormal social behavior in mice. Lu et al., 2017 also identified loss-of-function variants in CIC in five patients with similar clinical features, including developmental delay/intellectual disability, ASD/autistic features, and seizures.

4/1/2017
icon
2S

Increased from to 2S

Description

A de novo loss-of-function (LoF) variant in the CIC gene was first identified in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014). A second de novo LoF variant in this gene was identified by whole genome sequencing in an ASD proband from a simplex family as part of the MSSNG initiative in Yuen et al., 2017. Based on the discovery of two de novo LoF variants in ASD cases, a probability of LoF intolerance rate (pLI) > 0.9, and a higher-than expected mutation rate (a false discovery rate < 15%), CIC was determined to be an ASD candidate gene in Yuen et al., 2017. Lu et al., 2017 demonstrated that deletion of Cic from the developing mouse forebrain resulted in hyperactivity, impaired learning and memory, and abnormal maturation and maintainence of upper-layer cortical neurons, whereas deletion of Cic from the hypothalamus and medial amygdala resulted in abnormal social behavior in mice. Lu et al., 2017 also identified loss-of-function variants in CIC in five patients with similar clinical features, including developmental delay/intellectual disability, ASD/autistic features, and seizures.

Krishnan Probability Score

Score 0.52813854445231

Ranking 1582/25841 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 0.99990294666404

Ranking 674/18225 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
Iossifov Probability Score

Score 0.937

Ranking 98/239 scored genes


[Show Scoring Methodology]
Supplementary dataset S2 in the paper by Iossifov et al. (PNAS 112, E5600-E5607 (2015)) lists 239 genes with a probability of at least 0.8 of being associated with autism risk (column I). This probability metric combines the evidence from de novo likely-gene- disrupting and missense mutations and assesses it against the background mutation rate in unaffected individuals from the University of Washington’s Exome Variant Sequence database (evs.gs.washington.edu/EVS/). The list of probability scores can be found here: www.pnas.org/lookup/suppl/doi:10.1073/pnas.1516376112/- /DCSupplemental/pnas.1516376112.sd02.xlsx
Sanders TADA Score

Score 0.69031812599129

Ranking 1098/18665 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 0.43008652689634

Ranking 1117/20870 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.
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