Human Gene Module / Chromosome 20 / SLC12A5

SLC12A5Solute carrier family 12 (potassium/chloride transporter), member 5

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
4 / 10
Rare Variants / Common Variants
20 / 0
Aliases
SLC12A5, KCC2
Associated Syndromes
-
Chromosome Band
20q13.12
Associated Disorders
SCZ
Relevance to Autism

Functionally-impairing missense variants in the SLC12A5 previously observed in epilepsy cases were identified in probands from a Quebec ASD cohort. Subsequent analysis of a combined dataset indicated that there was an enrichment of coding variants in the target region of the C-terminus of KCC2 in ASD cases compared to controls (P=0.03); this statistically significant enrichment increased when considering variants in this region that either disrupted or introduced a CpG site (P=6.8E-03) (Merner et al., 2015).

Molecular Function

This gene encodes an integral membrane K-Cl cotransporter that mediates electroneutral potassium-chloride cotransport in mature neurons and is important for Cl-homeostasis in neurons. Mutations in this gene have been associated with febrile seizures (Puskarjov et al., 2014), idiopathic generalized epilepsy (Kahle et al., 2014), and epilepsy of infancy with migrating focal seizures (Stodberg et al., 2015).

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to SLC12A5 (10 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support A variant of KCC2 from patients with febrile seizures impairs neuronal Cl- extrusion and dendritic spine formation Puskarjov M , et al. (2014) No -
2 Support Genetically encoded impairment of neuronal KCC2 cotransporter function in human idiopathic generalized epilepsy Kahle KT , et al. (2014) No -
3 Support Mutations in SLC12A5 in epilepsy of infancy with migrating focal seizures Stdberg T , et al. (2015) No -
4 Primary Regulatory domain or CpG site variation in SLC12A5, encoding the chloride transporter KCC2, in human autism and schizophrenia Merner ND , et al. (2015) Yes SCZ
5 Support Exonic Mosaic Mutations Contribute Risk for Autism Spectrum Disorder Krupp DR , et al. (2017) Yes -
6 Support - Rodin RE et al. (2021) Yes -
7 Support - Herrmann T et al. (2022) No -
8 Support - N.Y.) (07/2) No -
9 Support - Zhou X et al. (2022) Yes -
10 Support - Axel Schmidt et al. (2024) No -
Rare Variants   (20)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.923C>T p.Pro308Leu missense_variant De novo - - 35901164 N.Y.) (07/2)
c.1936C>T p.Leu646Phe stop_gained De novo - - 35982159 Zhou X et al. (2022)
c.1079G>A p.Arg360Gln missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.2276A>C p.Glu759Ala missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.2017C>T p.Gln673Ter stop_gained Unknown - - 39039281 Axel Schmidt et al. (2024)
c.2924G>A p.Arg975His missense_variant Unknown - - 24928908 Kahle KT , et al. (2014)
c.3214C>T p.Arg1072Cys missense_variant Unknown - - 24928908 Kahle KT , et al. (2014)
c.2924G>A p.Arg975His missense_variant Unknown - - 26528127 Merner ND , et al. (2015)
c.2874T>C p.Asp958= synonymous_variant Unknown - - 26528127 Merner ND , et al. (2015)
c.3211C>T p.Arg1071Trp missense_variant Unknown - - 26528127 Merner ND , et al. (2015)
c.3214C>T p.Arg1072Cys missense_variant Unknown - - 26528127 Merner ND , et al. (2015)
c.3030G>A p.Pro1010= synonymous_variant Unknown - - 26528127 Merner ND , et al. (2015)
c.626C>T p.Pro209Leu missense_variant Unknown - - 39039281 Axel Schmidt et al. (2024)
c.2548G>A p.Asp850Asn missense_variant De novo - Simplex 28867142 Krupp DR , et al. (2017)
c.1277T>C p.Leu426Pro missense_variant Familial - Multiplex 26333769 Stdberg T , et al. (2015)
c.1652G>A p.Gly551Asp missense_variant Familial - Multiplex 26333769 Stdberg T , et al. (2015)
c.2924G>A p.Arg975His missense_variant Familial Paternal Simplex 24668262 Puskarjov M , et al. (2014)
c.932T>A p.Leu311His missense_variant Familial Both parents Multiplex 26333769 Stdberg T , et al. (2015)
c.2855G>A,c.2924G>A p.Arg952His, p.Arg975His missense_variant Unknown - - 26528127 Merner ND , et al. (2015)
ENSG00000124140:ENST00000243964:exon21:c.G2735A:p.R912H,ENSG00000124140:ENST00000454036:exon21:c.G28 - missense_variant De novo - - 33432195 Rodin RE et al. (2021)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

Functionally-impairing missense variants in the SLC12A5 previously observed in epilepsy cases were identified in probands from a Quebec ASD cohort. Subsequent analysis of a combined dataset indicated that there was an enrichment of coding variants in the target region of the C-terminus of KCC2 in ASD cases compared to controls (P=0.03); this statistically significant enrichment increased when considering variants in this region that either disrupted or introduced a CpG site (P=6.8E-03) (Merner et al., 2015). Mutations in this gene have been associated with febrile seizures (Puskarjov et al., 2014), idiopathic generalized epilepsy (Kahle et al., 2014), and epilepsy of infancy with migrating focal seizures (Stodberg et al., 2015).

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.

1/1/2021
2
icon
2

Score remained at 2

Description

Functionally-impairing missense variants in the SLC12A5 previously observed in epilepsy cases were identified in probands from a Quebec ASD cohort. Subsequent analysis of a combined dataset indicated that there was an enrichment of coding variants in the target region of the C-terminus of KCC2 in ASD cases compared to controls (P=0.03); this statistically significant enrichment increased when considering variants in this region that either disrupted or introduced a CpG site (P=6.8E-03) (Merner et al., 2015). Mutations in this gene have been associated with febrile seizures (Puskarjov et al., 2014), idiopathic generalized epilepsy (Kahle et al., 2014), and epilepsy of infancy with migrating focal seizures (Stodberg et al., 2015).

Reports Added
[The landscape of somatic mutation in cerebral cortex of autistic and neurotypical individuals revealed by ultra-deep whole-genome sequencing2021]
10/1/2019
3
icon
2

Decreased from 3 to 2

New Scoring Scheme
Description

Functionally-impairing missense variants in the SLC12A5 previously observed in epilepsy cases were identified in probands from a Quebec ASD cohort. Subsequent analysis of a combined dataset indicated that there was an enrichment of coding variants in the target region of the C-terminus of KCC2 in ASD cases compared to controls (P=0.03); this statistically significant enrichment increased when considering variants in this region that either disrupted or introduced a CpG site (P=6.8E-03) (Merner et al., 2015). Mutations in this gene have been associated with febrile seizures (Puskarjov et al., 2014), idiopathic generalized epilepsy (Kahle et al., 2014), and epilepsy of infancy with migrating focal seizures (Stodberg et al., 2015).

Reports Added
[New Scoring Scheme]
10/1/2017
3
icon
3

Decreased from 3 to 3

Description

Functionally-impairing missense variants in the SLC12A5 previously observed in epilepsy cases were identified in probands from a Quebec ASD cohort. Subsequent analysis of a combined dataset indicated that there was an enrichment of coding variants in the target region of the C-terminus of KCC2 in ASD cases compared to controls (P=0.03); this statistically significant enrichment increased when considering variants in this region that either disrupted or introduced a CpG site (P=6.8E-03) (Merner et al., 2015). Mutations in this gene have been associated with febrile seizures (Puskarjov et al., 2014), idiopathic generalized epilepsy (Kahle et al., 2014), and epilepsy of infancy with migrating focal seizures (Stodberg et al., 2015).

Reports Added
[Exonic Mosaic Mutations Contribute Risk for Autism Spectrum Disorder.2017]
10/1/2015
icon
3

Increased from to 3

Description

Functionally-impairing missense variants in the SLC12A5 previously observed in epilepsy cases were identified in probands from a Quebec ASD cohort. Subsequent analysis of a combined dataset indicated that there was an enrichment of coding variants in the target region of the C-terminus of KCC2 in ASD cases compared to controls (P=0.03); this statistically significant enrichment increased when considering variants in this region that either disrupted or introduced a CpG site (P=6.8E-03) (Merner et al., 2015). Mutations in this gene have been associated with febrile seizures (Puskarjov et al., 2014), idiopathic generalized epilepsy (Kahle et al., 2014), and epilepsy of infancy with migrating focal seizures (Stodberg et al., 2015).

Krishnan Probability Score

Score 0.61607469145303

Ranking 103/25841 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 0.99998727249691

Ranking 473/18225 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 0.94420663101931

Ranking 15985/18665 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 0.37621312358875

Ranking 1719/20870 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
Submit New Gene

Report an Error