Human Gene Module / Chromosome 5 / PCDHAC2

PCDHAC2Protocadherin alpha subfamily C, 2

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
2 / 4
Rare Variants / Common Variants
2 / 2
Aliases
PCDHAC2, PCDH-ALPHA-C2
Associated Syndromes
-
Chromosome Band
5q31.3
Associated Disorders
-
Relevance to Autism

Two SNPs within PCDHAC2 (rs155806 and rs17119346) showed significant association with autism in a family-based association study using 14 SNPs within the PCDHA gene cluster in 841 ASD families (574 of which were multiplex) obtained from the Autism Genetic Resource Exchange (AGRE) (Anitha et al., 2012).

Molecular Function

This gene is a member of the protocadherin alpha gene cluster, one of three related gene clusters tandemly linked on chromosome five that demonstrate an unusual genomic organization similar to that of B-cell and T-cell receptor gene clusters. The alpha gene cluster is composed of 15 cadherin superfamily genes related to the mouse CNR genes and consists of 13 highly similar and 2 more distantly related coding sequences. The tandem array of 15 N-terminal exons, or variable exons, are followed by downstream C-terminal exons, or constant exons, which are shared by all genes in the cluster. The large, uninterrupted N-terminal exons each encode six cadherin ectodomains while the C-terminal exons encode the cytoplasmic domain. These neural cadherin-like cell adhesion proteins are integral plasma membrane proteins that most likely play a critical role in the establishment and function of specific cell-cell connections in the brain.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
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Reports related to PCDHAC2 (4 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Recent Recommendation Identification of CTCF as a master regulator of the clustered protocadherin genes Golan-Mashiach M , et al. (2012) No -
2 Primary Protocadherin ? (PCDHA) as a novel susceptibility gene for autism Anitha A , et al. (2012) Yes -
3 Recent Recommendation Systems genetics identifies a convergent gene network for cognition and neurodevelopmental disease Johnson MR , et al. (2015) No -
4 Support - Woodbury-Smith M et al. (2022) Yes -
Rare Variants   (2)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.233G>A p.Arg78His missense_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.1757A>T p.Asn586Ile missense_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
Common Variants   (2)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
c.2713+11686G>A - intron_variant - - - 23031252 Anitha A , et al. (2012)
c.2565+924A>G T/C intron_variant - - - 23031252 Anitha A , et al. (2012)
SFARI Gene score
2

Strong Candidate

Two SNPs within PCDHAC2 (rs155806 and rs17119346) showed significant association with autism in a family-based association study using 14 SNPs within the PCDHA gene cluster in 841 ASD families (574 of which were multiplex) obtained from the Autism Genetic Resource Exchange (AGRE) (Anitha et al., 2012).

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 SNPs within PCDHAC2 (rs155806 and rs17119346) showed significant association with autism in a family-based association study using 14 SNPs within the PCDHA gene cluster in 841 ASD families (574 of which were multiplex) obtained from the Autism Genetic Resource Exchange (AGRE) (Anitha et al., 2012).

10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

Two SNPs within PCDHAC2 (rs155806 and rs17119346) showed significant association with autism in a family-based association study using 14 SNPs within the PCDHA gene cluster in 841 ASD families (574 of which were multiplex) obtained from the Autism Genetic Resource Exchange (AGRE) (Anitha et al., 2012).

Reports Added
[New Scoring Scheme]
7/1/2018
icon
4

Increased from to 4

Description

Two SNPs within PCDHAC2 (rs155806 and rs17119346) showed significant association with autism in a family-based association study using 14 SNPs within the PCDHA gene cluster in 841 ASD families (574 of which were multiplex) obtained from the Autism Genetic Resource Exchange (AGRE) (Anitha et al., 2012).

Krishnan Probability Score

Score 0.55529621212688

Ranking 1347/25841 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 0.91696611187088

Ranking 3066/18225 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 0.9426462294463

Ranking 15385/18665 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 2

Ranking 403/461 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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