Human Gene Module / Chromosome 12 / KCNC2

KCNC2potassium voltage-gated channel subfamily C member 2

SFARI Gene Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
8 / 13
Rare Variants / Common Variants
41 / 0
Aliases
-
Associated Syndromes
-
Chromosome Band
12q21.1
Associated Disorders
-
Relevance to Autism

De novo variants in the KCNC2 gene, including a missense variant that was predicted to be deleterious, have been identified in ASD probands (Yuen et al., 2017; Turner et al., 2017; Satterstrom et al., 2020), while an inherited loss-of-function variant in this gene was reported in an ASD proband from the iHART cohort (Ruzzo et al.,2019). De novo variants in this gene have also been implicated in several forms of epilepsy, including developmental and epileptic encephalopathy (Vetri et al., 2020; Rydzanicz et al., 2021) and West syndrome (Rademacher et al., 2020), and other developmental disorders (Kaplanis et al., 2020). More recently, Schwarz et al., 2022 identified.novel KCNC2 variants in 18 patients with various forms of epilepsy, and functional analysis of four of the variants reported in this paper demonstrated gain-of-function in three severely affected cases with developmental and epileptic encephalopathy and loss-of-function in one case with genetic generalized epilepsy; one of the gain-of-function variants was identified de novo in a patient who also presented with autism spectrum disorder. Mehniovic et al., 2022 reported a de novo likely germline mosaic missense variant in KCNC2 that was observed in two female siblings affected by autism, epileptic encephalopathy, developmental delay, and cognitive impairment; in the same report, a literature review identified additional individuals with neurodevelopmental disorders with a missense variant in this gene (de novo missense p-value 1.03E-05).

Molecular Function

The Shaker gene family of Drosophila encodes components of voltage-gated potassium channels and is comprised of four subfamilies. Based on sequence similarity, this gene is similar to one of these subfamilies, namely the Shaw subfamily. The protein encoded by this gene belongs to the delayed rectifier class of channel proteins and is an integral membrane protein that mediates the voltage-dependent potassium ion permeability of excitable membranes.

External Links
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Human
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SFARI Genomic Platforms
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Reports related to KCNC2 (13 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder C Yuen RK et al. (2017) Yes -
2 Support Genomic Patterns of De Novo Mutation in Simplex Autism Turner TN et al. (2017) Yes -
3 Support Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks Ruzzo EK , et al. (2019) Yes -
4 Support - Vetri L et al. (2020) No -
5 Primary Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
6 Support - Rademacher A et al. (2020) No -
7 Support - Kaplanis J et al. (2020) No -
8 Support - Rydzanicz M et al. (2021) No -
9 Recent Recommendation - Schwarz N et al. (2022) No ASD, ID
10 Recent Recommendation - Mehinovic E et al. (2022) Yes -
11 Support - Cirnigliaro M et al. (2023) Yes -
12 Support - Sheth F et al. (2023) Yes DD, ID
13 Support - Jerome Clatot et al. (2024) Yes -
Rare Variants   (41)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- p.Arg351Lys missense_variant De novo - - 35314505 Schwarz N et al. (2022)
- p.Asn530His missense_variant Unknown - - 35314505 Schwarz N et al. (2022)
- p.Asp128Glu missense_variant Unknown - - 35314505 Schwarz N et al. (2022)
- p.Asp167Tyr missense_variant De novo - - 35314505 Schwarz N et al. (2022)
- p.Cys125Trp missense_variant De novo - - 35314505 Schwarz N et al. (2022)
- p.Glu135Gly missense_variant De novo - - 35314505 Schwarz N et al. (2022)
- p.Phe382Cys missense_variant De novo - - 35314505 Schwarz N et al. (2022)
- p.Thr437Ala missense_variant De novo - - 35314505 Schwarz N et al. (2022)
- p.Thr437Asn missense_variant De novo - - 35314505 Schwarz N et al. (2022)
- p.Thr32Ala missense_variant Familial Maternal - 35314505 Schwarz N et al. (2022)
c.687+30624G>A - intron_variant De novo - Simplex 28263302 C Yuen RK et al. (2017)
c.687+15691T>A - intron_variant De novo - Simplex 28965761 Turner TN et al. (2017)
c.687+48174A>C - intron_variant De novo - Simplex 28965761 Turner TN et al. (2017)
c.688-29871C>T - intron_variant De novo - Simplex 28965761 Turner TN et al. (2017)
c.688-43660T>A - intron_variant De novo - Simplex 28965761 Turner TN et al. (2017)
c.*431T>C - 3_prime_UTR_variant De novo - Simplex 28263302 C Yuen RK et al. (2017)
- p.Ser333Thr missense_variant Familial Maternal - 35314505 Schwarz N et al. (2022)
- p.Val330Met missense_variant Familial Maternal - 35314505 Schwarz N et al. (2022)
- p.Arg351Lys missense_variant De novo - Multiplex 35314505 Schwarz N et al. (2022)
- p.Phe219Ser missense_variant De novo - Multiplex 35314505 Schwarz N et al. (2022)
c.687+40100G>A - intron_variant De novo - Multiplex 28263302 C Yuen RK et al. (2017)
c.687+65193C>A - intron_variant De novo - Multiplex 28263302 C Yuen RK et al. (2017)
c.687+69934C>T - intron_variant De novo - Multiplex 28263302 C Yuen RK et al. (2017)
c.687+75089A>G - intron_variant De novo - Multiplex 28263302 C Yuen RK et al. (2017)
c.688-39058del - intron_variant De novo - Multiplex 28263302 C Yuen RK et al. (2017)
c.499G>T p.Asp167Tyr missense_variant De novo - - 32392612 Rademacher A et al. (2020)
c.47G>A p.Gly16Asp missense_variant De novo - - 31981491 Satterstrom FK et al. (2020)
c.374G>A p.Cys125Tyr missense_variant De novo - - 38194456 Jerome Clatot et al. (2024)
c.688T>G p.Phe230Val missense_variant Unknown - Simplex 37543562 Sheth F et al. (2023)
c.1411G>C p.Val471Leu missense_variant De novo - Simplex 31972370 Vetri L et al. (2020)
c.1309A>G p.Thr437Ala missense_variant De novo - Simplex 33057194 Kaplanis J et al. (2020)
c.1384G>A p.Val462Met missense_variant De novo - Simplex 33057194 Kaplanis J et al. (2020)
c.1391C>T p.Thr464Ile missense_variant De novo - Simplex 33057194 Kaplanis J et al. (2020)
c.1736C>T p.Thr579Met missense_variant De novo - Simplex 33057194 Kaplanis J et al. (2020)
- p.Ser636Phe missense_variant Familial Maternal Multiplex 35314505 Schwarz N et al. (2022)
- p.Asp144Glu missense_variant Unknown - Extended multiplex 35314505 Schwarz N et al. (2022)
- p.Ile465Val missense_variant Unknown - Extended multiplex 35314505 Schwarz N et al. (2022)
c.1411G>C p.Val471Leu missense_variant De novo - Simplex 34448338 Rydzanicz M et al. (2021)
c.*495G>T - splice_site_variant Familial Paternal Multiplex 37506195 Cirnigliaro M et al. (2023)
c.1726_1727dup p.Leu577SerfsTer3 frameshift_variant Familial Paternal Multiplex 31398340 Ruzzo EK , et al. (2019)
c.1418T>C p.Val473Ala missense_variant De novo (germline mosaicism) - Multiplex 35366058 Mehinovic E et al. (2022)
Common Variants  

No common variants reported.

SFARI Gene score
3

Suggestive Evidence

Score Delta: Score remained at 3

criteria met
See SFARI Gene'scoring criteria
3

Suggestive Evidence

See all Category 3 Genes

The literature is replete with relatively small studies of candidate genes, using either common or rare variant approaches, which do not reach the criteria set out for categories 1 and 2. Genes that had two such lines of supporting evidence were placed in category 3, and those with one line of evidence were placed in category 4. Some additional lines of "accessory evidence" (indicated as "acc" in the score cards) could also boost a gene from category 4 to 3.

4/1/2022
icon
3

Increased from to 3

Krishnan Probability Score

Score 0.4905262109146

Ranking 6079/25841 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 0.0035968182193055

Ranking 10845/18225 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 0.93929807364735

Ranking 14161/18665 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 0.005617981988774

Ranking 8519/20870 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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