Human Gene Module / Chromosome 19 / CC2D1A

CC2D1ACoiled-coil and C2 domain containing 1A

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
7 / 18
Rare Variants / Common Variants
19 / 0
Aliases
CC2D1A, FREUD-1,  Freud-1/Aki1,  MRT3
Associated Syndromes
-
Chromosome Band
19p13.12
Associated Disorders
ASD, EPS, ID
Relevance to Autism

Autosomal-recessive "founder" mutations in the CC2D1A gene were identified in 4 families with a total of 16 individuals affected by a spectrum of cognitive and social impairments, including ASD, non-syndromic ID, and seizures (Manzini et al., 2014).

Molecular Function

This gene encodes a transcriptional repressor that binds specifically to the DRE (dual repressor element) and represses HTR1A gene transcription in neuronal cells. Performs an essential function in controlling the functional maturation of synapses. Mutations in this gene are associated with mental retardation, autosomal recessive 3 (MRT3) [MIM:608443], a non-syndromic disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
Mouse
Entrez GeneMouse Genome Informatics
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to CC2D1A (18 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Highly Cited The CC2D1A, a member of a new gene family with C2 domains, is involved in autosomal recessive non-syndromic mental retardation Basel-Vanagaite L , et al. (2005) No -
2 Support Genetic screening for autosomal recessive nonsyndromic mental retardation in an isolated population in Israel Basel-Vanagaite L , et al. (2006) No -
3 Support Cc2d1a, a C2 domain containing protein linked to nonsyndromic mental retardation, controls functional maturation of central synapses Zhao M , et al. (2011) No -
4 Primary CC2D1A regulates human intellectual and social function as well as NF-?B signaling homeostasis Manzini MC , et al. (2014) Yes Epilepsy/seizures
5 Support The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
6 Support The roles of CC2D1A and HTR1A gene expressions in autism spectrum disorders Sener EF , et al. (2016) Yes -
7 Recent Recommendation Cc2d1a Loss of Function Disrupts Functional and Morphological Development in Forebrain Neurons Leading to Cognitive and Social Deficits Oaks AW , et al. (2016) No -
8 Support Identification of a RAI1-associated disease network through integration of exome sequencing, transcriptomics, and 3D genomics Loviglio MN , et al. (2016) No -
9 Support Diagnostic Yield and Novel Candidate Genes by Exome Sequencing in 152 Consanguineous Families With Neurodevelopmental Disorders Reuter MS , et al. (2017) No Aggressive behavior
10 Support Identification of candidate gene FAM183A and novel pathogenic variants in known genes: High genetic heterogeneity for autosomal recessive intellectual disability McSherry M , et al. (2018) No ASD or autistic features, seizures
11 Support Neurological Diseases With Autism Spectrum Disorder: Role of ASD Risk Genes Xiong J , et al. (2019) Yes ID
12 Support Lessons Learned from Large-Scale, First-Tier Clinical Exome Sequencing in a Highly Consanguineous Population Monies D , et al. (2019) No -
13 Support The diagnostic yield of intellectual disability: combined whole genome low-coverage sequencing and medical exome sequencing Wang J et al. (2020) No -
14 Support - Yang CY et al. (2021) Yes -
15 Support - Zhou X et al. (2022) Yes -
16 Support - Costa CIS et al. (2023) Yes -
17 Support - Sanchis-Juan A et al. (2023) No -
18 Support - et al. () No Autistic features
Rare Variants   (19)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.380C>T p.Pro127Leu missense_variant Unknown - - 31031587 Xiong J , et al. (2019)
c.748+1G>T - splice_site_variant - Both parents - 31130284 Monies D , et al. (2019)
c.2074-27G>A - intron_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.2728G>A p.Glu910Lys missense_variant Unknown - - 31031587 Xiong J , et al. (2019)
c.1641+1G>A - splice_site_variant Familial Both parents Multiplex 38375126 et al. ()
c.1552G>T p.Glu518Ter stop_gained De novo - Simplex 25363768 Iossifov I et al. (2014)
c.1739C>T p.Thr580Ile missense_variant Unknown - - 27799067 Loviglio MN , et al. (2016)
c.2657G>A p.Arg886His missense_variant Unknown - - 27799067 Loviglio MN , et al. (2016)
c.270G>C p.Glu90Asp missense_variant Familial Paternal - 32429945 Wang J et al. (2020)
- - copy_number_loss Familial Both parents Simplex 37541188 Sanchis-Juan A et al. (2023)
c.2342G>T p.Gly781Val missense_variant Familial Maternal - 32429945 Wang J et al. (2020)
c.1647G>T p.Pro549%3D synonymous_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.2244C>G p.Asp748Glu missense_variant Familial Maternal Simplex 37280359 Costa CIS et al. (2023)
c.748+1G>T - splice_site_variant Familial Both parents Multiplex 25066123 Manzini MC , et al. (2014)
c.2693del p.Gly898ValfsTer45 frameshift_variant Familial Both parents Multiplex 28097321 Reuter MS , et al. (2017)
c.347del p.Lys116ArgfsTer82 frameshift_variant Familial Both parents Multiplex 25066123 Manzini MC , et al. (2014)
c.811del p.Ala271ProfsTer30 frameshift_variant Familial Both parents Multiplex 30500859 McSherry M , et al. (2018)
IVS13_IVS16del p.Gly408fsTer437 copy_number_loss Familial Both parents Simplex 16033914 Basel-Vanagaite L , et al. (2005)
IVS13_IVS16del p.Gly408fsTer437 copy_number_loss Familial Both parents Multiplex 16033914 Basel-Vanagaite L , et al. (2005)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

Homozygous loss-of-variant (LoF) variants in the CC2D1A gene were identified in four families with a total of 16 individuals affected with a variable spectrum of presentations including intellectual disability, ASD, and seizures. A splice-site variant in CC2D1A was observed in two related families with at least one ASD case, while a frameshift variant in CC2D1A was observed in another family with an ASD case (PMID 25066123). Homozygous LoF deletions in CC2D1A have previously been identified in patients with non-syndromic intellectual disability (PMID 16033914). Conditional postnatal removal of CC2D1A in mouse forebrain neurons resulted in abnormal cortical dendrite organization and a reduction in dendritic spine density, as well as deficits in neuronal plasticity and in spatial learning and memory that were accompanied by reduced sociability, hyperactivity, anxiety, and excessive grooming (Oaks et al., 2016).

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.

4/1/2020
2
icon
2

Score remained at 2

Description

Homozygous loss-of-variant (LoF) variants in the CC2D1A gene were identified in four families with a total of 16 individuals affected with a variable spectrum of presentations including intellectual disability, ASD, and seizures. A splice-site variant in CC2D1A was observed in two related families with at least one ASD case, while a frameshift variant in CC2D1A was observed in another family with an ASD case (PMID 25066123). Homozygous LoF deletions in CC2D1A have previously been identified in patients with non-syndromic intellectual disability (PMID 16033914). Conditional postnatal removal of CC2D1A in mouse forebrain neurons resulted in abnormal cortical dendrite organization and a reduction in dendritic spine density, as well as deficits in neuronal plasticity and in spatial learning and memory that were accompanied by reduced sociability, hyperactivity, anxiety, and excessive grooming (Oaks et al., 2016).

Reports Added
[The diagnostic yield of intellectual disability: combined whole genome low-coverage sequencing and medical exome sequencing2020]
10/1/2019
3
icon
2

Decreased from 3 to 2

New Scoring Scheme
Description

Homozygous loss-of-variant (LoF) variants in the CC2D1A gene were identified in four families with a total of 16 individuals affected with a variable spectrum of presentations including intellectual disability, ASD, and seizures. A splice-site variant in CC2D1A was observed in two related families with at least one ASD case, while a frameshift variant in CC2D1A was observed in another family with an ASD case (PMID 25066123). Homozygous LoF deletions in CC2D1A have previously been identified in patients with non-syndromic intellectual disability (PMID 16033914). Conditional postnatal removal of CC2D1A in mouse forebrain neurons resulted in abnormal cortical dendrite organization and a reduction in dendritic spine density, as well as deficits in neuronal plasticity and in spatial learning and memory that were accompanied by reduced sociability, hyperactivity, anxiety, and excessive grooming (Oaks et al., 2016).

Reports Added
[New Scoring Scheme]
7/1/2019
3
icon
3

Decreased from 3 to 3

Description

Homozygous loss-of-variant (LoF) variants in the CC2D1A gene were identified in four families with a total of 16 individuals affected with a variable spectrum of presentations including intellectual disability, ASD, and seizures. A splice-site variant in CC2D1A was observed in two related families with at least one ASD case, while a frameshift variant in CC2D1A was observed in another family with an ASD case (PMID 25066123). Homozygous LoF deletions in CC2D1A have previously been identified in patients with non-syndromic intellectual disability (PMID 16033914). Conditional postnatal removal of CC2D1A in mouse forebrain neurons resulted in abnormal cortical dendrite organization and a reduction in dendritic spine density, as well as deficits in neuronal plasticity and in spatial learning and memory that were accompanied by reduced sociability, hyperactivity, anxiety, and excessive grooming (Oaks et al., 2016).

Reports Added
[Lessons Learned from Large-Scale, First-Tier Clinical Exome Sequencing in a Highly Consanguineous Population.2019]
4/1/2019
3
icon
3

Decreased from 3 to 3

Description

Homozygous loss-of-variant (LoF) variants in the CC2D1A gene were identified in four families with a total of 16 individuals affected with a variable spectrum of presentations including intellectual disability, ASD, and seizures. A splice-site variant in CC2D1A was observed in two related families with at least one ASD case, while a frameshift variant in CC2D1A was observed in another family with an ASD case (PMID 25066123). Homozygous LoF deletions in CC2D1A have previously been identified in patients with non-syndromic intellectual disability (PMID 16033914). Conditional postnatal removal of CC2D1A in mouse forebrain neurons resulted in abnormal cortical dendrite organization and a reduction in dendritic spine density, as well as deficits in neuronal plasticity and in spatial learning and memory that were accompanied by reduced sociability, hyperactivity, anxiety, and excessive grooming (Oaks et al., 2016).

Reports Added
[Neurological Diseases With Autism Spectrum Disorder: Role of ASD Risk Genes.2019]
10/1/2018
3
icon
3

Decreased from 3 to 3

Description

Homozygous loss-of-variant (LoF) variants in the CC2D1A gene were identified in four families with a total of 16 individuals affected with a variable spectrum of presentations including intellectual disability, ASD, and seizures. A splice-site variant in CC2D1A was observed in two related families with at least one ASD case, while a frameshift variant in CC2D1A was observed in another family with an ASD case (PMID 25066123). Homozygous LoF deletions in CC2D1A have previously been identified in patients with non-syndromic intellectual disability (PMID 16033914). Conditional postnatal removal of CC2D1A in mouse forebrain neurons resulted in abnormal cortical dendrite organization and a reduction in dendritic spine density, as well as deficits in neuronal plasticity and in spatial learning and memory that were accompanied by reduced sociability, hyperactivity, anxiety, and excessive grooming (Oaks et al., 2016).

Reports Added
[Identification of candidate gene FAM183A and novel pathogenic variants in known genes: High genetic heterogeneity for autosomal recessive intellect...2018]
1/1/2017
3
icon
3

Decreased from 3 to 3

Description

Homozygous loss-of-variant (LoF) variants in the CC2D1A gene were identified in four families with a total of 16 individuals affected with a variable spectrum of presentations including intellectual disability, ASD, and seizures. A splice-site variant in CC2D1A was observed in two related families with at least one ASD case, while a frameshift variant in CC2D1A was observed in another family with an ASD case (PMID 25066123). Homozygous LoF deletions in CC2D1A have previously been identified in patients with non-syndromic intellectual disability (PMID 16033914). Conditional postnatal removal of CC2D1A in mouse forebrain neurons resulted in abnormal cortical dendrite organization and a reduction in dendritic spine density, as well as deficits in neuronal plasticity and in spatial learning and memory that were accompanied by reduced sociability, hyperactivity, anxiety, and excessive grooming (Oaks et al., 2016).

Reports Added
[Diagnostic Yield and Novel Candidate Genes by Exome Sequencing in 152 Consanguineous Families With Neurodevelopmental Disorders.2017]
10/1/2016
3
icon
3

Decreased from 3 to 3

Description

Homozygous loss-of-variant (LoF) variants in the CC2D1A gene were identified in four families with a total of 16 individuals affected with a variable spectrum of presentations including intellectual disability, ASD, and seizures. A splice-site variant in CC2D1A was observed in two related families with at least one ASD case, while a frameshift variant in CC2D1A was observed in another family with an ASD case (PMID 25066123). Homozygous LoF deletions in CC2D1A have previously been identified in patients with non-syndromic intellectual disability (PMID 16033914). Conditional postnatal removal of CC2D1A in mouse forebrain neurons resulted in abnormal cortical dendrite organization and a reduction in dendritic spine density, as well as deficits in neuronal plasticity and in spatial learning and memory that were accompanied by reduced sociability, hyperactivity, anxiety, and excessive grooming (Oaks et al., 2016).

Reports Added
[Identification of a RAI1-associated disease network through integration of exome sequencing, transcriptomics, and 3D genomics.2016]
1/1/2016
3
icon
3

Decreased from 3 to 3

Description

Homozygous loss-of-variant (LoF) variants in the CC2D1A gene were identified in four families with a total of 16 individuals affected with a variable spectrum of presentations including intellectual disability, ASD, and seizures. A splice-site variant in CC2D1A was observed in two related families with at least one ASD case, while a frameshift variant in CC2D1A was observed in another family with an ASD case (PMID 25066123). Homozygous LoF deletions in CC2D1A have previously been identified in patients with non-syndromic intellectual disability (PMID 16033914).

Reports Added
[CC2D1A regulates human intellectual and social function as well as NF-B signaling homeostasis.2014] [The CC2D1A, a member of a new gene family with C2 domains, is involved in autosomal recessive non-syndromic mental retardation.2005] [Genetic screening for autosomal recessive nonsyndromic mental retardation in an isolated population in Israel.2006] [Cc2d1a, a C2 domain containing protein linked to nonsyndromic mental retardation, controls functional maturation of central synapses.2011] [The contribution of de novo coding mutations to autism spectrum disorder2014] [Cc2d1a Loss of Function Disrupts Functional and Morphological Development in Forebrain Neurons Leading to Cognitive and Social Deficits.2016] [The roles of CC2D1A and HTR1A gene expressions in autism spectrum disorders.2016]
7/1/2014
icon
3

Increased from to 3

Description

Homozygous loss-of-variant (LoF) variants in the CC2D1A gene were identified in four families with a total of 16 individuals affected with a variable spectrum of presentations including intellectual disability, ASD, and seizures. A splice-site variant in CC2D1A was observed in two related families with at least one ASD case, while a frameshift variant in CC2D1A was observed in another family with an ASD case (PMID 25066123). Homozygous LoF deletions in CC2D1A have previously been identified in patients with non-syndromic intellectual disability (PMID 16033914).

Krishnan Probability Score

Score 0.44967316545492

Ranking 11073/25841 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 2.2592026083696E-5

Ranking 13827/18225 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 0.49478040618037

Ranking 437/18665 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
Larsen Cumulative Evidence Score

Score 36

Ranking 59/461 scored genes


[Show Scoring Methodology]
Larsen and colleagues generated gene scores based on the sum of evidence for all available ASD-associated variants in a gene, with assessments based on mode of inheritance, effect size, and variant frequency in the general population. The approach was first presented in Mol Autism 7:44 (2016), and scores for 461 genes can be found in column I in supplementary table 4 from that paper.
Original Source
Zhang D Score

Score 0.26639710440878

Ranking 3236/20870 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
Interactome
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
CDC37 cell division cycle 37 Human Protein Binding 11140 Q16543
Champ4b charged multivesicular body protein 4B Mouse Protein Binding 75608 Q9D8B3
CHMP4A charged multivesicular body protein 4A Human Protein Binding 29082 Q9BY43
CHMP4C charged multivesicular body protein 4C Human Protein Binding 92421 Q96CF2
CRYAB Alpha-crystallin B chain Human Protein Binding 1410 P02511
MRAP2 melanocortin 2 receptor accessory protein 2 Human Protein Binding 112609 Q96G30
NRF1 nuclear respiratory factor 1 Human DNA Binding 4899 Q16656
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