Human Gene Module / Chromosome 11 / KCNC1

KCNC1potassium voltage-gated channel subfamily C member 1

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
5 / 10
Rare Variants / Common Variants
8 / 0
Aliases
KCNC1, EPM7,  KV3.1,  KV4,  NGK2
Associated Syndromes
-
Chromosome Band
11p15.1
Associated Disorders
-
Relevance to Autism

De novo missense variants in the KCNC1 gene were identified in two ASD probands (Iossifov et al., 2014; Yuen et al., 2017) and a proband with an unspecified developmental disorder (Deciphering Developmental Disorders Study 2017). An integrated meta-analysis of de novo mutation data from a combined dataset of 10,927 individuals with neurodevelopmental disorders identified KCNC1 as a gene with an excess of missense variants (false discovery rata < 5%, count >1) (Coe et al., 2018).

Molecular Function

This gene encodes a member of a family of integral membrane proteins that mediate the voltage-dependent potassium ion permeability of excitable membranes; this channel plays an important role in the rapid repolarization of fast-firing brain neurons.

External Links
Gene CardOpen Targets PlatformgnomAD browserSynGO portalPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to KCNC1 (10 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
2 Support Prevalence and architecture of de novo mutations in developmental disorders et al. (2017) No -
3 Support Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder C Yuen RK et al. (2017) Yes -
4 Recent Recommendation Neurodevelopmental disease genes implicated by de novo mutation and copy number variation morbidity Coe BP , et al. (2018) No -
5 Support Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks Ruzzo EK , et al. (2019) Yes -
6 Support - Bee S et al. (2021) Yes -
7 Support - Zhou X et al. (2022) Yes -
8 Support - Sanchis-Juan A et al. (2023) No -
9 Support - Ko YJ et al. (2023) No ID
10 Support - Tamam Khalaf et al. (2024) No -
Rare Variants   (8)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.1262C>T p.Ala421Val missense_variant De novo - - 28135719 et al. (2017)
c.1262C>T p.Ala421Val missense_variant Unknown - - 37645600 Ko YJ et al. (2023)
c.959G>A p.Arg320His missense_variant De novo - Simplex 37645600 Ko YJ et al. (2023)
c.1694-6A>G - splice_region_variant De novo - Multiplex 35982159 Zhou X et al. (2022)
c.1262C>T p.Ala421Val missense_variant Unknown - - 38438125 Tamam Khalaf et al. (2024)
c.889G>A p.Gly297Ser missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.1249G>T p.Gly417Trp missense_variant De novo - Multiplex 28263302 C Yuen RK et al. (2017)
c.121G>A p.Asp41Asn missense_variant Unknown - Simplex 37541188 Sanchis-Juan A et al. (2023)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

De novo missense variants in the KCNC1 gene were identified in two ASD probands (Iossifov et al., 2014; Yuen et al., 2017) and a proband with an unspecified developmental disorder (Deciphering Developmental Disorders Study 2017). An integrated meta-analysis of de novo mutation data from a combined dataset of 10,927 individuals with neurodevelopmental disorders identified KCNC1 as a gene with an excess of missense variants (false discovery rata < 5%, count >1) (Coe et al., 2018).

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

De novo missense variants in the KCNC1 gene were identified in two ASD probands (Iossifov et al., 2014; Yuen et al., 2017) and a proband with an unspecified developmental disorder (Deciphering Developmental Disorders Study 2017). An integrated meta-analysis of de novo mutation data from a combined dataset of 10,927 individuals with neurodevelopmental disorders identified KCNC1 as a gene with an excess of missense variants (false discovery rata < 5%, count >1) (Coe et al., 2018).

10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

De novo missense variants in the KCNC1 gene were identified in two ASD probands (Iossifov et al., 2014; Yuen et al., 2017) and a proband with an unspecified developmental disorder (Deciphering Developmental Disorders Study 2017). An integrated meta-analysis of de novo mutation data from a combined dataset of 10,927 individuals with neurodevelopmental disorders identified KCNC1 as a gene with an excess of missense variants (false discovery rata < 5%, count >1) (Coe et al., 2018).

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

Decreased from 4 to 4

Description

De novo missense variants in the KCNC1 gene were identified in two ASD probands (Iossifov et al., 2014; Yuen et al., 2017) and a proband with an unspecified developmental disorder (Deciphering Developmental Disorders Study 2017). An integrated meta-analysis of de novo mutation data from a combined dataset of 10,927 individuals with neurodevelopmental disorders identified KCNC1 as a gene with an excess of missense variants (false discovery rata < 5%, count >1) (Coe et al., 2018).

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

Increased from to 4

Description

De novo missense variants in the KCNC1 gene were identified in two ASD probands (Iossifov et al., 2014; Yuen et al., 2017) and a proband with an unspecified developmental disorder (Deciphering Developmental Disorders Study 2017). An integrated meta-analysis of de novo mutation data from a combined dataset of 10,927 individuals with neurodevelopmental disorders identified KCNC1 as a gene with an excess of missense variants (false discovery rata < 5%, count >1) (Coe et al., 2018).

Krishnan Probability Score

Score 0.59154895545022

Ranking 475/25841 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 0.70997213579973

Ranking 4430/18225 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 0.78872665010133

Ranking 2026/18665 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 0.59203756461963

Ranking 105/20870 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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