Human Gene Module / Chromosome 2 / CNTNAP5

CNTNAP5contactin associated protein-like 5

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
11 / 16
Rare Variants / Common Variants
18 / 5
Aliases
CNTNAP5, caspr5
Associated Syndromes
-
Chromosome Band
2q14.3
Associated Disorders
DD/NDD, ID, ASD
Relevance to Autism

Rare mutations in the CNTNAP5 gene have been identified with autism in an IMGSAC cohort (Pagnamenta et al., 2010) as well as in two siblings with autism (Vaags et al., 2012). In addition, genetic association has been found of the CNTNAP5 gene with bipolar disorder (in Norwegian and Icelandic cohorts) as well as with treatment response in schizophrenic patients.

Molecular Function

A multidomain transmembrane protein involved in cell adhesion and intercellular communication

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to CNTNAP5 (16 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Highly Cited New members of the neurexin superfamily: multiple rodent homologues of the human CASPR5 gene Traut W , et al. (2006) No -
2 Recent Recommendation Genome-wide pharmacogenomic analysis of response to treatment with antipsychotics McClay JL , et al. (2009) No -
3 Primary Characterization of a family with rare deletions in CNTNAP5 and DOCK4 suggests novel risk loci for autism and dyslexia Pagnamenta AT , et al. (2010) Yes Dyslexia
4 Recent Recommendation A genome-wide association study of bipolar disorder in Norwegian individuals, followed by replication in Icelandic sample Djurovic S , et al. (2010) No -
5 Support Rare deletions at the neurexin 3 locus in autism spectrum disorder Vaags AK , et al. (2012) Yes -
6 Support Application of array comparative genomic hybridization in 102 patients with epilepsy and additional neurodevelopmental disorders Bartnik M , et al. (2012) No ASD, DD, ID
7 Support A discovery resource of rare copy number variations in individuals with autism spectrum disorder Prasad A , et al. (2013) Yes -
8 Positive Association A candidate gene association study further corroborates involvement of contactin genes in autism Poot M (2014) Yes -
9 Negative Association No evidence for association of autism with rare heterozygous point mutations in Contactin-Associated Protein-Like 2 (CNTNAP2), or in Other Contactin-Associated Proteins or Contactins Murdoch JD , et al. (2015) Yes -
10 Support Mutations in Human Accelerated Regions Disrupt Cognition and Social Behavior Doan RN , et al. (2016) Yes -
11 Support Next-generation DNA sequencing identifies novel gene variants and pathways involved in specific language impairment Chen XS , et al. (2017) No -
12 Support Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks Ruzzo EK , et al. (2019) Yes -
13 Support Autism spectrum disorder and intellectual disability in an inherited 2q14.3 micro-deletion involving CNTNAP5 Aleo S et al. (2020) Yes DD, ID
14 Support - Zhou X et al. (2022) Yes -
15 Support - Hu C et al. (2023) Yes -
16 Support - Sheth F et al. (2023) Yes DD, ID
Rare Variants   (18)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
insT - intergenic_variant - - Unknown 27667684 Doan RN , et al. (2016)
- - copy_number_loss Unknown - Unknown 23275889 Prasad A , et al. (2013)
- - copy_number_gain Familial Maternal - 22825934 Bartnik M , et al. (2012)
- - copy_number_loss Familial Maternal Simplex 32975021 Aleo S et al. (2020)
- - copy_number_loss Familial Maternal Unknown 23275889 Prasad A , et al. (2013)
c.1483G>A p.Asp495Asn missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.2150T>C p.Val717Ala missense_variant Unknown - - 28440294 Chen XS , et al. (2017)
- - copy_number_loss Familial Paternal Multiplex 20346443 Pagnamenta AT , et al. (2010)
c.1240G>C p.Gly414Arg missense_variant Familial Maternal - 37007974 Hu C et al. (2023)
c.326T>C p.Met109Thr missense_variant Unknown - Simplex 37543562 Sheth F et al. (2023)
c.3680A>T p.Glu1227Val missense_variant Familial Paternal - 37007974 Hu C et al. (2023)
c.2141C>G p.Pro714Arg missense_variant De novo - - 20346443 Pagnamenta AT , et al. (2010)
c.2756C>T p.Thr919Met missense_variant De novo - - 20346443 Pagnamenta AT , et al. (2010)
c.1023T>C p.Ile341%3D synonymous_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.3502G>A p.Val1168Ile missense_variant De novo - - 20346443 Pagnamenta AT , et al. (2010)
c.3584C>T p.Thr1195Met missense_variant De novo - - 20346443 Pagnamenta AT , et al. (2010)
c.2868C>A p.Cys956Ter stop_gained Familial Maternal Multiplex 31398340 Ruzzo EK , et al. (2019)
c.3701G>A p.Arg1234Gln missense_variant Familial Paternal Multiplex 22209245 Vaags AK , et al. (2012)
Common Variants   (5)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
c.2074+19018A>G;c.2077+19018A>G Allele 1, A; allele 2, G intron_variant - - - 25337070 Poot M (2014)
c.83-63639G>T - intron_variant - - - 20451256 Djurovic S , et al. (2010)
c.83-69281A>G - intron_variant - - - 20451256 Djurovic S , et al. (2010)
c.83-63121C>A N/A intron_variant - - - 20451256 Djurovic S , et al. (2010)
c.1355C>T;c.1358C>T p.Ser452Leu missense_variant - - - 19721433 McClay JL , et al. (2009)
SFARI Gene score
2

Strong Candidate

Rare mutations in the CNTNAP5 gene have been identified with autism in an IMGSAC cohort (Pagnamenta et al., 2010) as well as in two siblings with autism (Vaags et al., 2012). In addition, genetic association has been found of the CNTNAP5 gene with bipolar disorder (in Norwegian and Icelandic cohorts) as well as with treatment reponse in schizophrenic patients.

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

Rare mutations in the CNTNAP5 gene have been identified with autism in an IMGSAC cohort (Pagnamenta et al., 2010) as well as in two siblings with autism (Vaags et al., 2012). In addition, genetic association has been found of the CNTNAP5 gene with bipolar disorder (in Norwegian and Icelandic cohorts) as well as with treatment reponse in schizophrenic patients.

7/1/2020
3
icon
3

Decreased from 3 to 3

Description

Rare mutations in the CNTNAP5 gene have been identified with autism in an IMGSAC cohort (Pagnamenta et al., 2010) as well as in two siblings with autism (Vaags et al., 2012). In addition, genetic association has been found of the CNTNAP5 gene with bipolar disorder (in Norwegian and Icelandic cohorts) as well as with treatment reponse in schizophrenic patients.

Reports Added
[Clustering by phenotype and genome-wide association study in autism2020]
10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

Rare mutations in the CNTNAP5 gene have been identified with autism in an IMGSAC cohort (Pagnamenta et al., 2010) as well as in two siblings with autism (Vaags et al., 2012). In addition, genetic association has been found of the CNTNAP5 gene with bipolar disorder (in Norwegian and Icelandic cohorts) as well as with treatment reponse in schizophrenic patients.

Reports Added
[New Scoring Scheme]
7/1/2019
4
icon
4

Decreased from 4 to 4

Description

Rare mutations in the CNTNAP5 gene have been identified with autism in an IMGSAC cohort (Pagnamenta et al., 2010) as well as in two siblings with autism (Vaags et al., 2012). In addition, genetic association has been found of the CNTNAP5 gene with bipolar disorder (in Norwegian and Icelandic cohorts) as well as with treatment reponse in schizophrenic patients.

Reports Added
[Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks.2019]
4/1/2017
4
icon
4

Decreased from 4 to 4

Description

Rare mutations in the CNTNAP5 gene have been identified with autism in an IMGSAC cohort (Pagnamenta et al., 2010) as well as in two siblings with autism (Vaags et al., 2012). In addition, genetic association has been found of the CNTNAP5 gene with bipolar disorder (in Norwegian and Icelandic cohorts) as well as with treatment reponse in schizophrenic patients.

Reports Added
[Characterization of a family with rare deletions in CNTNAP5 and DOCK4 suggests novel risk loci for autism and dyslexia.2010] [Rare deletions at the neurexin 3 locus in autism spectrum disorder.2012] [A discovery resource of rare copy number variations in individuals with autism spectrum disorder.2013] [A candidate gene association study further corroborates involvement of contactin genes in autism.2014] [No evidence for association of autism with rare heterozygous point mutations in Contactin-Associated Protein-Like 2 (CNTNAP2), or in Other Contacti...2015] [A genome-wide association study of bipolar disorder in Norwegian individuals, followed by replication in Icelandic sample.2010] [Application of array comparative genomic hybridization in 102 patients with epilepsy and additional neurodevelopmental disorders.2012] [Genome-wide pharmacogenomic analysis of response to treatment with antipsychotics.2009] [New members of the neurexin superfamily: multiple rodent homologues of the human CASPR5 gene.2006] [Mutations in Human Accelerated Regions Disrupt Cognition and Social Behavior.2016] [Next-generation DNA sequencing identifies novel gene variants and pathways involved in specific language impairment.2017]
10/1/2016
4
icon
4

Decreased from 4 to 4

Description

Rare mutations in the CNTNAP5 gene have been identified with autism in an IMGSAC cohort (Pagnamenta et al., 2010) as well as in two siblings with autism (Vaags et al., 2012). In addition, genetic association has been found of the CNTNAP5 gene with bipolar disorder (in Norwegian and Icelandic cohorts) as well as with treatment reponse in schizophrenic patients.

Reports Added
[Mutations in Human Accelerated Regions Disrupt Cognition and Social Behavior.2016]
1/1/2015
4
icon
4

Decreased from 4 to 4

Description

Rare mutations in the CNTNAP5 gene have been identified with autism in an IMGSAC cohort (Pagnamenta et al., 2010) as well as in two siblings with autism (Vaags et al., 2012). In addition, genetic association has been found of the CNTNAP5 gene with bipolar disorder (in Norwegian and Icelandic cohorts) as well as with treatment reponse in schizophrenic patients.

Reports Added
[No evidence for association of autism with rare heterozygous point mutations in Contactin-Associated Protein-Like 2 (CNTNAP2), or in Other Contacti...2015]
10/1/2014
4
icon
4

Decreased from 4 to 4

Description

Rare mutations in the CNTNAP5 gene have been identified with autism in an IMGSAC cohort (Pagnamenta et al., 2010) as well as in two siblings with autism (Vaags et al., 2012). In addition, genetic association has been found of the CNTNAP5 gene with bipolar disorder (in Norwegian and Icelandic cohorts) as well as with treatment reponse in schizophrenic patients.

Reports Added
[A candidate gene association study further corroborates involvement of contactin genes in autism.2014]
7/1/2014
No data
icon
4

Increased from No data to 4

Description

Rare mutations in the CNTNAP5 gene have been identified with autism in an IMGSAC cohort (Pagnamenta et al., 2010) as well as in two siblings with autism (Vaags et al., 2012). In addition, genetic association has been found of the CNTNAP5 gene with bipolar disorder (in Norwegian and Icelandic cohorts) as well as with treatment reponse in schizophrenic patients.

4/1/2014
No data
icon
4

Increased from No data to 4

Description

Rare mutations in the CNTNAP5 gene have been identified with autism in an IMGSAC cohort (Pagnamenta et al., 2010) as well as in two siblings with autism (Vaags et al., 2012). In addition, genetic association has been found of the CNTNAP5 gene with bipolar disorder (in Norwegian and Icelandic cohorts) as well as with treatment reponse in schizophrenic patients.

Krishnan Probability Score

Score 0.49575027839885

Ranking 2817/25841 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 0.097272924280362

Ranking 7891/18225 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 0.94584216221207

Ranking 16631/18665 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 14

Ranking 135/461 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
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