Human Gene Module / Chromosome 7 / KCND2

KCND2potassium voltage-gated channel subfamily D member 2

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
4 / 9
Rare Variants / Common Variants
14 / 4
Aliases
KCND2, KV4.2,  RK5
Associated Syndromes
-
Chromosome Band
7q31.31
Associated Disorders
-
Relevance to Autism

A de novo missense variant (p.Val404Met) was identified in the KCND2 gene in monozygotic twins affected with autism and severe, intractable seizures; functional analysis revealed the likely pathogenicity of this variant in that the p.Val404Met construct showed significantly slowed inactivation, consistent with a gain-of-function effect (PMID 24501278). In a genome-wide association study of 2165 participants from the Autism Genetic Resource Exchange (AGRE) performed to examine associations between genomic loci and endophenotypes associated with ASDs, it was shown that item 46 ("has overly serious facial expressions") on the Social Responsiveness Scale (SRS) significantly associates with the gene KCND2 (Connolly et al., 2012).

Molecular Function

Voltage-gated potassium (Kv) channels represent the most complex class of voltage-gated ion channels from both functional and structural standpoints. Their diverse functions include regulating neurotransmitter release, heart rate, insulin secretion, neuronal excitability, epithelial electrolyte transport, smooth muscle contraction, and cell volume. Four sequence-related potassium channel genes - shaker, shaw, shab, and shal - have been identified in Drosophila, and each has been shown to have human homolog(s). This gene encodes a member of the potassium channel, voltage-gated, shal-related subfamily, members of which form voltage-activated A-type potassium ion channels and are prominent in the repolarization phase of the action potential. This member mediates a rapidly inactivating, A-type outward potassium current which is not under the control of the N terminus as it is in Shaker channels.

External Links
Gene CardOpen Targets PlatformgnomAD browserSynGO portalPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to KCND2 (9 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Exome sequencing of ion channel genes reveals complex profiles confounding personal risk assessment in epilepsy Klassen T , et al. (2011) No -
2 Primary A genome-wide association study of autism incorporating autism diagnostic interview-revised, autism diagnostic observation schedule, and social responsiveness scale Connolly JJ , et al. (2012) Yes -
3 Recent Recommendation Exome sequencing identifies de novo gain of function missense mutation in KCND2 in identical twins with autism and seizures that slows potassium channel inactivation Lee H , et al. (2014) Yes -
4 Support The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies Redin C , et al. (2016) No CHD (Atrial septal defect)
5 Support Kv4.2 autism and epilepsy mutation enhances inactivation of closed channels but impairs access to inactivated state after opening Lin MA , et al. (2018) No -
6 Support De Novo Sequence and Copy Number Variants Are Strongly Associated with Tourette Disorder and Implicate Cell Polarity in Pathogenesis Wang S , et al. (2018) No -
7 Support - Zhang Y et al. (2021) No ASD, epilepsy/seizures
8 Support - Zhou X et al. (2022) Yes -
9 Positive Association - Liu Z et al. (2023) Yes -
Rare Variants   (14)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - translocation De novo - - 27841880 Redin C , et al. (2016)
c.331_332insAA p.Cys111Ter stop_gained De novo - - 35982159 Zhou X et al. (2022)
c.967G>A p.Glu323Lys missense_variant Unknown - - 34245260 Zhang Y et al. (2021)
c.1207C>G p.Pro403Ala missense_variant De novo - - 34245260 Zhang Y et al. (2021)
c.1207C>G p.Pro403Ala missense_variant Unknown - - 34245260 Zhang Y et al. (2021)
c.1210G>A p.Val404Met missense_variant De novo - - 34245260 Zhang Y et al. (2021)
c.1210G>C p.Val404Leu missense_variant De novo - - 34245260 Zhang Y et al. (2021)
c.1210G>T p.Val404Leu missense_variant De novo - - 34245260 Zhang Y et al. (2021)
c.1015G>A p.Ala339Thr missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.1270G>A p.Ala424Thr missense_variant De novo - Simplex 30257206 Wang S , et al. (2018)
c.432C>T p.Asn144= synonymous_variant Unknown - Unknown 21703448 Klassen T , et al. (2011)
c.670C>A p.Arg224= synonymous_variant Unknown - Unknown 21703448 Klassen T , et al. (2011)
c.1616G>T p.Arg539Leu missense_variant Unknown - Unknown 21703448 Klassen T , et al. (2011)
c.1210G>A p.Val404Met missense_variant De novo - Multiplex (monozygotic twins) 24501278 Lee H , et al. (2014)
Common Variants   (4)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
- - intergenic_variant - - - 22935194 Connolly JJ , et al. (2012)
c.1115+18046A>G - intron_variant - - - 36756634 Liu Z et al. (2023)
c.1115+27310A>G - intron_variant - - - 36756634 Liu Z et al. (2023)
c.1115+91454A>T - intron_variant - - - 36756634 Liu Z et al. (2023)
SFARI Gene score
2

Strong Candidate

A de novo missense variant (p.Val404Met) was identified in the KCND2 gene in monozygotic twins affected with autism and severe, intractable seizures; functional analysis revealed the likely pathogenicity of this variant in that the p.Val404Met construct showed significantly slowed inactivation, consistent with a gain-of-function effect (PMID 24501278). In a genome-wide association study of 2165 participants from the Autism Genetic Resource Exchange (AGRE) performed to examine associations between genomic loci and endophenotypes associated with ASDs, it was shown that item 46 ("has overly serious facial expressions") on the Social Responsiveness Scale (SRS) significantly associates with the gene KCND2 (Connolly 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

A de novo missense variant (p.Val404Met) was identified in the KCND2 gene in monozygotic twins affected with autism and severe, intractable seizures; functional analysis revealed the likely pathogenicity of this variant in that the p.Val404Met construct showed significantly slowed inactivation, consistent with a gain-of-function effect (PMID 24501278). In a genome-wide association study of 2165 participants from the Autism Genetic Resource Exchange (AGRE) performed to examine associations between genomic loci and endophenotypes associated with ASDs, it was shown that item 46 ("has overly serious facial expressions") on the Social Responsiveness Scale (SRS) significantly associates with the gene KCND2 (Connolly et al., 2012).

10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

A de novo missense variant (p.Val404Met) was identified in the KCND2 gene in monozygotic twins affected with autism and severe, intractable seizures; functional analysis revealed the likely pathogenicity of this variant in that the p.Val404Met construct showed significantly slowed inactivation, consistent with a gain-of-function effect (PMID 24501278). In a genome-wide association study of 2165 participants from the Autism Genetic Resource Exchange (AGRE) performed to examine associations between genomic loci and endophenotypes associated with ASDs, it was shown that item 46 ("has overly serious facial expressions") on the Social Responsiveness Scale (SRS) significantly associates with the gene KCND2 (Connolly et al., 2012).

Reports Added
[New Scoring Scheme]
10/1/2018
4
icon
4

Decreased from 4 to 4

Description

A de novo missense variant (p.Val404Met) was identified in the KCND2 gene in monozygotic twins affected with autism and severe, intractable seizures; functional analysis revealed the likely pathogenicity of this variant in that the p.Val404Met construct showed significantly slowed inactivation, consistent with a gain-of-function effect (PMID 24501278). In a genome-wide association study of 2165 participants from the Autism Genetic Resource Exchange (AGRE) performed to examine associations between genomic loci and endophenotypes associated with ASDs, it was shown that item 46 ("has overly serious facial expressions") on the Social Responsiveness Scale (SRS) significantly associates with the gene KCND2 (Connolly et al., 2012).

Reports Added
[De Novo Sequence and Copy Number Variants Are Strongly Associated with Tourette Disorder and Implicate Cell Polarity in Pathogenesis.2018]
7/1/2018
icon
4

Increased from to 4

Description

A de novo missense variant (p.Val404Met) was identified in the KCND2 gene in monozygotic twins affected with autism and severe, intractable seizures; functional analysis revealed the likely pathogenicity of this variant in that the p.Val404Met construct showed significantly slowed inactivation, consistent with a gain-of-function effect (PMID 24501278). In a genome-wide association study of 2165 participants from the Autism Genetic Resource Exchange (AGRE) performed to examine associations between genomic loci and endophenotypes associated with ASDs, it was shown that item 46 ("has overly serious facial expressions") on the Social Responsiveness Scale (SRS) significantly associates with the gene KCND2 (Connolly et al., 2012).

Krishnan Probability Score

Score 0.60786250630986

Ranking 299/25841 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 0.98046083226404

Ranking 2118/18225 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 0.93464007014299

Ranking 12630/18665 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 22.5

Ranking 89/461 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 0.44798399706391

Ranking 944/20870 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
BAG1 Human Protein Binding
KCNE4 Potassium voltage-gated channel subfamily E member 4 Human Protein Binding 23704 Q8WWG9
KCNIP1 Kv channel-interacting protein 1 Human Protein Binding 30820 Q9NZI2
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