Human Gene Module / Chromosome 1 / KCNA2

KCNA2potassium voltage-gated channel subfamily A member 2

SFARI Gene Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
4 / 12
Rare Variants / Common Variants
23 / 0
Aliases
-
Associated Syndromes
-
Chromosome Band
1p13.3
Associated Disorders
-
Relevance to Autism

Whole-genome sequencing of a cohort of 30 adults with unexplained developmental and epileptic encephalopathies in Qaiser et al., 2021 identified three individuals with potentially pathogenic KCNA2 variants; all three of these patients presented with seizures, intellectual disability, and autism spectrum disorder. Autism spectrum disorder has previously been reported in a subset of individuals with KCNA2-associated movement disorders (Helbig et al., 2016; Ngo et al., 2020). An inherited frameshift variant in KCNA2 has also been identified in an ASD proband from the iHART cohort (Ruzzo et al., 2019).

Molecular Function

Potassium 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, shaker-related subfamily. This member contains six membrane-spanning domains with a shaker-type repeat in the fourth segment. It belongs to the delayed rectifier class, members of which allow nerve cells to efficiently repolarize following an action potential. Heterozygous mutations in this gene are responsible for a form of developmental and epileptic encephalopathy [Developmental and epileptic encephalopathy 32 (DEE32); OMIM 6163

External Links
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Human
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SFARI Genomic Platforms
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Reports related to KCNA2 (12 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support - Pena SD et al. (2015) No -
2 Support - Syrbe S et al. (2015) No DD
3 Support - Helbig KL et al. (2016) No ASD, DD, epilepsy/seizures
4 Support Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks Ruzzo EK , et al. (2019) Yes -
5 Support - Ngo KJ et al. (2020) No ASD
6 Primary - Qaiser F et al. (2021) Yes DD
7 Support - Woodbury-Smith M et al. (2022) Yes -
8 Support - Chuan Z et al. (2022) No -
9 Support - Balasar et al. (2023) No -
10 Support - Sheth F et al. (2023) Yes DD, ID, epilepsy/seizures
11 Support - Teresa Mínguez-Viñas et al. (2023) No ASD, ID
12 Support - Hosneara Akter et al. () No -
Rare Variants   (23)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.890G>A p.Arg297Gln missense_variant Unknown - - 31692161 Ngo KJ et al. (2020)
c.440G>A p.Arg147Lys missense_variant Unknown - - 25751627 Syrbe S et al. (2015)
c.529A>G p.Ile177Val missense_variant Unknown - - 35571021 Chuan Z et al. (2022)
c.894+320C>T - missense_variant De novo - Simplex 25751627 Syrbe S et al. (2015)
c.547G>A p.Glu183Lys missense_variant De novo - - 34622207 Qaiser F et al. (2021)
c.894+440del - frameshift_variant Unknown - Unknown 34622207 Qaiser F et al. (2021)
c.890G>A p.Arg297Gln missense_variant De novo - Simplex 31692161 Ngo KJ et al. (2020)
c.890G>T p.Arg297Leu missense_variant De novo - Simplex 25477152 Pena SD et al. (2015)
c.788T>C p.Ile263Thr missense_variant De novo - Simplex 25751627 Syrbe S et al. (2015)
c.890G>A p.Arg297Gln missense_variant De novo - Simplex 25751627 Syrbe S et al. (2015)
c.894G>T p.Leu298Phe missense_variant De novo - Simplex 25751627 Syrbe S et al. (2015)
c.1214C>T p.Pro405Leu missense_variant De novo - Simplex 25751627 Syrbe S et al. (2015)
c.890G>A p.Arg297Gln missense_variant De novo - Simplex 34622207 Qaiser F et al. (2021)
c.1214C>T p.Pro405Leu missense_variant Unknown - Simplex 37524782 Balasar et al. (2023)
c.881G>A p.Arg294His missense_variant De novo - Multiplex 27543892 Helbig KL et al. (2016)
c.932del p.Gly311GlufsTer5 frameshift_variant Unknown - - 39342494 Hosneara Akter et al. ()
c.798C>T p.Tyr266%3D synonymous_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.511A>G p.Met171Val missense_variant Familial Paternal Simplex 37543562 Sheth F et al. (2023)
c.881G>A p.Arg294His missense_variant Familial Maternal Simplex 27543892 Helbig KL et al. (2016)
c.106del p.Val36Ter frameshift_variant Familial Maternal Multiplex 31398340 Ruzzo EK , et al. (2019)
c.928C>T p.His310Tyr missense_variant Unknown - Multiplex 37883018 Teresa Mínguez-Viñas et al. (2023)
c.929A>G p.His310Arg missense_variant Unknown Not maternal - 37883018 Teresa Mínguez-Viñas et al. (2023)
c.881G>A p.Arg294His missense_variant Familial Maternal Multi-generational 27543892 Helbig KL et al. (2016)
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.

1/1/2023
S
icon
3

Increased from S to 3

Krishnan Probability Score

Score 0.49681076859251

Ranking 2508/25841 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 0.88417395644561

Ranking 3350/18225 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 0.9276709738076

Ranking 10727/18665 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 0.18332594233347

Ranking 4542/20870 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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