SLC12A5
protein-codingsolute carrier family 12 member 5, the group of Solute carrier family 12
Gene summary
K-Cl cotransporters are proteins that lower intracellular chloride concentrations below the electrochemical equilibrium potential. The protein encoded by this gene is an integral membrane K-Cl cotransporter that can function in either a net efflux or influx pathway, depending on the chemical concentration gradients of potassium and chloride. The encoded protein can act as a homomultimer, or as a heteromultimer with other K-Cl cotransporters, to maintain chloride homeostasis in neurons. Alternative splicing results in two transcript variants encoding different isoforms. [provided by RefSeq, Sep 2008]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~38.5 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0014718
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0017385
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0014718
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0014734
Submitter: Illumina
Inheritance Pattern: AR
Disease ID:MONDO:0014718
Submitter: Illumina
Inheritance Pattern: AR
Disease ID:MONDO:0014718
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0100025
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0100062
Submitter: ClinGen
*SLC12A5* was first reported in relation to autosomal recessive developmental and epileptic encephalopathy in 2015 (Stödberg et al., PMID:26333769). Typical phenotypes of these probands include infantile-onset focal seizures, which are often epilepsy of infancy with migrating focal seizures, global developmental delay, hypotonia, progressive microcephaly, delayed myelination and cerebral atrophy (PMIDs: 26333769, 27436767, and 31618474). Of note, there has been an assertion made for autosomal dominant susceptibility to idiopathic generalized epilepsy (OMIM:616685). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in inheritance pattern and phenotypic variability. The Epilepsy GCEP does not curate for disease susceptibility, so the information about epilepsy susceptibility will not be curated at this time. This entry will only cover autosomal recessive developmental and epileptic encephalopathy (MONDO:0100062). Ten variants (missense, small in-frame deletions, and splicing) that have been reported in six probands in three publications (PMIDs: 26333769, 27436767, 31618474) are included in this curation. There is some preliminary evidence to suggest that the mechanism of pathogenicity may be loss of function. Electrophysiological studies showed reduced transporter activity of proteins with some variants, although few studies are available at this time (PMIDs: 26333769, 27436767). This gene-disease relationship is also supported by a knockout mouse model in which gentle handling or movement of the mother and littermates triggered seizures (PMID: 12000122). In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Epilepsy Gene Curation Expert Panel on March 7, 2023 (SOP Version 9).
Inheritance Pattern: AD
Disease ID:MONDO:0014734
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0014734
Submitter: Ambry Genetics
Clinical Genomic Database (CGD)
Manifestation: Neurologic
Intervention: General
Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to SLC12A5 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_020708.5. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 6 | 321 | 3 | 330 | ||
| missense | 1 | 5 | 351 | 9 | 366 | |
| nonsense | 11 | 2 | 1 | 14 | ||
| start loss | 0 | |||||
| frameshift | 19 | 1 | 20 | |||
| splice donor/acceptor (+/-2bp) | 9 | 2 | 11 | |||
| Total | 31 | 16 | 361 | 330 | 3 | 741 |
Highest pathogenic variant AF is 0.000001860839
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_065759.1 | 26 | MANE Select | |
| Ensembl | ENSP00000243964.4 | 26 | MANE Select | |
| RefSeq | NP_001128243.1 | 26 | Standard | |
| Ensembl | ENSP00000487291.1 | 3 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| slc12a5b | Danio rerio | Structure: retinal ganglion cell Quality: decreased functionality abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- GABAergic synapse - Homo sapiens (human)
- Cation-coupled Chloride cotransporters
- Transport of inorganic cations/anions and amino acids/oligopeptides
- SLC-mediated transmembrane transport
- Transport of small molecules
Biological Process
- ion transport
- cellular ion homeostasis
- cell volume homeostasis
- hypotonic response
- chemical synaptic transmission
Molecular Function
- chloride transmembrane transporter activity
- potassium:chloride symporter activity
Cellular Component
- plasma membrane
- integral component of plasma membrane
- integral component of membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000454036
- Coding exons
- 26
- Length
- 38429
- Individuals with no LoFs
- 125742
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 5
- Defined
- 125747
- p
- 0.0000199
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 4.70 | 347 | 696 | 0.498 | 0.0000404 | 7435 |
| Missense (PolyPhen) | 63 | 256.45 | 0.24566 | 2697 | ||
| Synonymous | 1.01 | 253 | 274 | 0.922 | 0.0000161 | 2301 |
| Loss of Function | 6.58 | 3 | 56.3 | 0.0533 | 0.00000295 | 621 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0.000029 | 0.000029 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00011 | 0.00011 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000018 | 0.000018 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Mediates electroneutral potassium-chloride cotransport in mature neurons and is required for neuronal Cl(-) homeostasis. As major extruder of intracellular chloride, it establishes the low neuronal Cl(-) levels required for chloride influx after binding of GABA-A and glycine to their receptors, with subsequent hyperpolarization and neuronal inhibition (By similarity). Involved in the regulation of dendritic spine formation and maturation (PubMed:24668262). {ECO:0000250|UniProtKB:Q63633, ECO:0000269|PubMed:24668262}.;
- Disease
- DISEASE: Epilepsy, idiopathic generalized 14 (EIG14) [MIM:616685]: An autosomal dominant form of idiopathic generalized epilepsy, a disorder characterized by recurring generalized seizures in the absence of detectable brain lesions and/or metabolic abnormalities. Generalized seizures arise diffusely and simultaneously from both hemispheres of the brain. Seizure types include juvenile myoclonic seizures, absence seizures, and generalized tonic-clonic seizures. {ECO:0000269|PubMed:24668262, ECO:0000269|PubMed:24928908, ECO:0000269|PubMed:26528127}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.153
Intolerance Scores
- LoFtool
- 0.00861
- RVIS EVS
- -1.37
- RVIS percentile EVS
- 4.45
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.366
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |