GeneBe

SLC12A6

protein-coding

solute carrier family 12 member 6, the group of Solute carrier family 12

Gene summary

This gene is a member of the K-Cl cotransporter (KCC) family. K-Cl cotransporters are integral membrane proteins that lower intracellular chloride concentrations below the electrochemical equilibrium potential. The proteins encoded by this gene are activated by cell swelling induced by hypotonic conditions. Alternate splicing results in multiple transcript variants encoding different isoforms. Mutations in this gene are associated with agenesis of the corpus callosum with peripheral neuropathy. [provided by RefSeq, Jul 2008]

Previous symbols:
  • KCC3
  • ACCPN

MANE transcript

NM_001365088.1

Inheritance

AD, AR

ClinVar variants

P:248U:508B:481

Top phenotype

Charcot-Marie-Tooth disease, axonal, type 2II; Agenesis of the corpus callosum with peripheral neuropathy (Andermann syndrome)

gnomAD constraint

pLI —, LoF o/e 0.26

Max pathogenic AF

—

Genomic locus

chr15:34,229,784-34,338,060

External References & Databases

Ensembl (ENSG00000140199)NCBI Gene (9990)OMIM (604878)HGNC:10914GenCCUniProt (Q9UHW9)AlphaFoldClinVar (SLC12A6)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~108.3 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Charcot-Marie-Tooth disease, axonal, IIa 2IISTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0031068

Submitter: Labcorp Genetics (formerly Invitae)

agenesis of the corpus callosum with peripheral neuropathyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0000902

Submitter: G2P

agenesis of the corpus callosum with peripheral neuropathySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0000902

Submitter: PanelApp Australia

Charcot-Marie-Tooth disease, axonal, IIa 2IIDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0031068

Submitter: Natera

agenesis of the corpus callosum with peripheral neuropathyLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0000902

Submitter: Ambry Genetics

agenesis of the corpus callosum with peripheral neuropathyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0000902

Submitter: Natera

Charcot-Marie-Tooth disease, axonal, IIa 2IISTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0031068

Submitter: PanelApp Australia

agenesis of the corpus callosum with peripheral neuropathySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0000902

Submitter: Orphanet

agenesis of the corpus callosum with peripheral neuropathySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0000902

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Charcot-Marie-Tooth disease, axonal, type 2II; Agenesis of the corpus callosum with peripheral neuropathy (Andermann syndrome)AD/AR

Manifestation: Craniofacial; Musculoskeletal; 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

Refs: 14397896; 6329500; 12368912; 12838516; 16606917; 17893295; 20020398; 20301546; 27485015; 31439721; 33323309; 34706912; 35733399Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SLC12A6 variants in ClinVar

16 Conditions Cataloged
not providedTotal: 1331
Agenesis of the corpus callosum with peripheral neuropathyTotal: 368
Inborn genetic diseasesTotal: 166
not specifiedTotal: 65
Charcot-Marie-Tooth disease, axonal, IIa 2IITotal: 35
SLC12A6-related disorderTotal: 24
Charcot-Marie-Tooth diseaseTotal: 9
Peripheral neuropathyTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001365088.1. 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.

EffectPLPVUSLBBSum
synonymous
1
clinvar
28
clinvar
464
clinvar
6
clinvar
 499
missense
5
clinvar
14
clinvar
464
clinvar
10
clinvar
1
clinvar
 494
nonsense
23
clinvar
36
clinvar
3
clinvar
 62
start loss
3
clinvar
 3
frameshift
31
clinvar
85
clinvar
2
clinvar
 118
splice donor/acceptor (+/-2bp)
5
clinvar
48
clinvar
8
clinvar
 61
Total6418450847471237

Highest pathogenic variant AF is 0.000028514187

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 30 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_001365088.1RefSeqNP_001352017.125MANE Select
ENST00000354181.8EnsemblENSP00000346112.325MANE Select
NM_001042494.2RefSeqNP_001035959.125Standard
NM_001042495.2RefSeqNP_001035960.125Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Polythiazide Action Pathway
  • Methyclothiazide Action Pathway
  • Bumetanide Action Pathway
  • Spironolactone Action Pathway
  • Eplerenone Action Pathway

Biological Process

  • angiogenesis
  • ion transport
  • cell volume homeostasis
  • chemical synaptic transmission
  • chloride ion homeostasis

Molecular Function

  • potassium:chloride symporter activity

Cellular Component

  • plasma membrane
  • integral component of plasma membrane
  • integral component of membrane
  • basolateral plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000354181
Coding exons
25
Length
104802
Individuals with no LoFs
125685
Homozygous LoFs
0
Heterozygous LoFs
63
Defined
125748
p
0.000251
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense2.964366480.6730.00003747527
Missense (PolyPhen)157327.530.479353835
Synonymous0.07602282290.9940.00001292293
Loss of Function5.491764.60.2630.00000415687

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000120.00012rare
Latino/Admixed American0.000670.00067rare
Ashkenazi Jewish0.000300.00030rare
East Asian0.000110.00011rare
Finnish0.000180.00018rare
European (Non-Finnish)0.000200.00020rare
South Asian0.000200.00020rare
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Mediates electroneutral potassium-chloride cotransport. May be activated by cell swelling. May contribute to cell volume homeostasis in single cells.;
Disease
DISEASE: Agenesis of the corpus callosum, with peripheral neuropathy (ACCPN) [MIM:218000]: A disease that is characterized by severe progressive sensorimotor neuropathy, mental retardation, dysmorphic features and complete or partial agenesis of the corpus callosum. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.262

Intolerance Scores

LoFtool
0.0254
RVIS EVS
-1.13
RVIS percentile EVS
6.51

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
N
Indispensability score
0.393

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
Feedback | API | Annotate VCF | Sitemap | About | Privacy & Terms
For research and educational, non-commercial use only. Not for clinical or diagnostic use. GeneBe does not provide medical advice. Data use for AI modeling is prohibited: if used, the cost is $0.001 per byte of downloaded uncompressed data.