Human Gene Module / Chromosome 5 / KCNN2

KCNN2potassium calcium-activated channel subfamily N member 2

SFARI Gene Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
3 / 4
Rare Variants / Common Variants
14 / 0
Aliases
-
Associated Syndromes
-
Chromosome Band
5q22.3
Associated Disorders
-
Relevance to Autism

Systematic investigation of the phenotypic and molecular genetic data of 1,577 patients from the TRANSLATE NAMSE cohort who had undergone exome sequencing and were partially analyzed with next-generation phenotypic approaches in Schmidt et al., 2024 identified a de novo missense variant in the KCNN2 gene in an adult female.with autism and specific learning disability. A de novo missense variant that was predicted to be deleterious and a de novo nonsense variant in KCNN2 have recently been reported in ASD probands (Zhou et al., 2022; Fu et al., 2022). Mochel et al., 2020 described individuals with KCNN2-associated neurodevelopmental disorder, which was characterized by developmental delay, intellectual disability, behavioral disturbances, and movement disorders; two out of 10 of these individuals were reported to have autism spectrum disorder, while autistic features were reported in four other cases. Subsequent functional assessment of six variants identified in affected individuals in this report by patch-clamp electrophysiology found that five resulted in loss-of-function effects.

Molecular Function

Action potentials in vertebrate neurons are followed by an afterhyperpolarization (AHP) that may persist for several seconds and may have profound consequences for the firing pattern of the neuron. Each component of the AHP is kinetically distinct and is mediated by different calcium-activated potassium channels. The protein encoded by this gene is activated before membrane hyperpolarization and is thought to regulate neuronal excitability by contributing to the slow component of synaptic AHP. This gene is a member of the KCNN family of potassium channel genes. The encoded protein is an integral membrane protein that forms a voltage-independent calcium-activated channel with three other calmodulin-binding subunits.

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Reports related to KCNN2 (4 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support - Fanny Mochel et al. (2020) No ASD or autistic features, ADHD, epilepsy/seizures
2 Support - Zhou X et al. (2022) Yes -
3 Support - Fu JM et al. (2022) Yes -
4 Primary - Axel Schmidt et al. (2024) Yes Learning disability
Rare Variants   (14)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.480C>A p.Tyr160Ter stop_gained De novo - - 35982160 Fu JM et al. (2022)
c.965G>C p.Trp322Ser missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.480C>A p.Tyr160Ter stop_gained De novo - - 33242881 Fanny Mochel et al. (2020)
c.1254+2T>C - splice_site_variant De novo - - 33242881 Fanny Mochel et al. (2020)
c.88G>C p.Glu30Gln missense_variant De novo - - 33242881 Fanny Mochel et al. (2020)
c.800_803del p.Tyr267Ter stop_gained De novo - - 33242881 Fanny Mochel et al. (2020)
c.863T>C p.Ile288Thr missense_variant De novo - - 39039281 Axel Schmidt et al. (2024)
c.1082A>G p.Tyr361Cys missense_variant De novo - - 33242881 Fanny Mochel et al. (2020)
c.1084G>A p.Gly362Ser missense_variant De novo - - 33242881 Fanny Mochel et al. (2020)
c.1162C>G p.Leu388Val missense_variant De novo - - 33242881 Fanny Mochel et al. (2020)
c.1077 T>G p.Ile359Met missense_variant De novo - - 33242881 Fanny Mochel et al. (2020)
c.962_964delTAT p.Leu321del inframe_deletion De novo - - 33242881 Fanny Mochel et al. (2020)
c.862_863delinsTC p.Ile288Ser missense_variant De novo - - 33242881 Fanny Mochel et al. (2020)
c.1295T>C p.Leu432Pro missense_variant Familial Maternal - 33242881 Fanny Mochel et al. (2020)
Common Variants  

No common variants reported.

SFARI Gene score
3

Suggestive Evidence

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.

10/1/2024
3

Initial score established: 3

Krishnan Probability Score

Score 0.49726348856137

Ranking 2415/25841 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 0.97104868857404

Ranking 2339/18225 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 0.8636394015261

Ranking 4005/18665 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 -0.1486810131094

Ranking 14087/20870 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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