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

Summary

Charcot-Marie-Tooth disease, axonal, IIa 2II (MONDO:0031068) is a disease caused by SLC12A6 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: SLC12A6 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 33

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Charcot-Marie-Tooth disease, axonal, IIa 2II
Mondo ID	MONDO:0031068
OMIM	620068
UMLS	C5774227
MedGen	1824000
GARD	0025691
Is cancer (heuristic)	no

Also known as: charcot-marie-tooth disease, axonal, IIa 2II · charcot-marie-tooth neuropathy, IIa 2II · CMT2II

Data availability: 33 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › peripheral nervous system disorder › peripheral neuropathy › hereditary peripheral neuropathy › Charcot-Marie-Tooth disease › Charcot-Marie-Tooth disease, axonal, IIa 2II

Related subtypes (23): Charcot-Marie-Tooth disease, Guadalajara neuronal type, Charcot-Marie-Tooth disease with ptosis and parkinsonism, Charcot-Marie-Tooth disease type 3, neuronopathy, distal hereditary motor, autosomal dominant 1, neuropathy, hereditary motor and sensory, type 6A, Charcot-Marie-Tooth disease, axonal, autosomal recessive, type 2a2b;, demyelinating hereditary motor and sensory neuropathy, intermediate Charcot-Marie-Tooth disease, Charcot-Marie-Tooth disease type 2, Charcot-Marie-Tooth disease type X, Charcot-Marie-Tooth disease type 4, Charcot-Marie-Tooth disease type 1, Charcot-Marie-Tooth disease, axonal, mitochondrial form, 1, Charcot-Marie-Tooth disease, axonal, type 2FF, Charcot-Marie-Tooth disease, axonal, Type 2HH, Charcot-Marie-Tooth disease, demyelinating, IIA 1I, Charcot-Marie-Tooth disease, demyelinating, IIA 1H, Charcot-Marie-Tooth disease, demyelinating, type 1G, Charcot-Marie-Tooth disease, demyelinating, type 1J, Charcot-Marie-tooth disease, axonal, type 2JJ, Charcot-Marie-Tooth disease, axonal, type 2KK, Charcot-Marie-Tooth disease, axonal, type 2LL, charcot-marie-tooth disease, axonal, type 2MM

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

33 retrieved; paginated sample, class counts are floors:

9 uncertain significance, 9 likely pathogenic, 6 pathogenic/likely pathogenic, 6 pathogenic, 3 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
1328560	NM_001365088.1(SLC12A6):c.1655G>A (p.Gly552Asp)	SLC12A6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1454158	NM_001365088.1(SLC12A6):c.2036A>G (p.Tyr679Cys)	SLC12A6	Pathogenic	criteria provided, single submitter
159897	NM_001365088.1(SLC12A6):c.379G>T (p.Glu127Ter)	SLC12A6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1708538	NM_001365088.1(SLC12A6):c.865G>A (p.Glu289Lys)	SLC12A6	Pathogenic	no assertion criteria provided
1708540	NM_001365088.1(SLC12A6):c.2036A>C (p.Tyr679Ser)	SLC12A6	Pathogenic	no assertion criteria provided
1987661	NM_001365088.1(SLC12A6):c.2002C>T (p.Arg668Ter)	SLC12A6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2678754	NM_001365088.1(SLC12A6):c.2272C>T (p.Gln758Ter)	SLC12A6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
436730	NM_001365088.1(SLC12A6):c.2436+1del	SLC12A6	Pathogenic	criteria provided, multiple submitters, no conflicts
521402	NM_001365088.1(SLC12A6):c.620G>A (p.Arg207His)	SLC12A6	Pathogenic	criteria provided, multiple submitters, no conflicts
5326	NM_001365088.1(SLC12A6):c.3031C>T (p.Arg1011Ter)	SLC12A6	Pathogenic	criteria provided, multiple submitters, no conflicts
835797	NM_001365088.1(SLC12A6):c.337C>T (p.Arg113Ter)	SLC12A6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
941545	NM_001365088.1(SLC12A6):c.316+1G>A	SLC12A6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1708535	NM_001365088.1(SLC12A6):c.2971A>G (p.Thr991Ala)	SLC12A6	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3577068	NM_001365088.1(SLC12A6):c.3254_3264delinsT (p.His1085fs)	SLC12A6	Likely pathogenic	criteria provided, single submitter
3577069	NM_001365088.1(SLC12A6):c.2162+2T>G	SLC12A6	Likely pathogenic	criteria provided, single submitter
3577070	NM_001365088.1(SLC12A6):c.1807delinsTTTCC (p.Ile603fs)	SLC12A6	Likely pathogenic	criteria provided, single submitter
3577071	NM_001365088.1(SLC12A6):c.1119-1G>C	SLC12A6	Likely pathogenic	criteria provided, single submitter
3577073	NM_001365088.1(SLC12A6):c.550del (p.Gln184fs)	SLC12A6	Likely pathogenic	criteria provided, single submitter
370235	NM_001365088.1(SLC12A6):c.2437-2A>G	SLC12A6	Likely pathogenic	criteria provided, multiple submitters, no conflicts
371054	NM_001365088.1(SLC12A6):c.3227+1G>A	SLC12A6	Likely pathogenic	criteria provided, multiple submitters, no conflicts
554561	NM_001365088.1(SLC12A6):c.3337C>T (p.Arg1113Ter)	SLC12A6	Likely pathogenic	criteria provided, single submitter
1708539	NM_001365088.1(SLC12A6):c.1728CTT[1] (p.Phe578del)	SLC12A6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
218665	NM_001365088.1(SLC12A6):c.271+17825C>T	SLC12A6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
315615	NM_001365088.1(SLC12A6):c.1250A>G (p.Asn417Ser)	SLC12A6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1304485	NM_001365088.1(SLC12A6):c.97C>G (p.Pro33Ala)	SLC12A6	Uncertain significance	criteria provided, multiple submitters, no conflicts
1786625	NM_001365088.1(SLC12A6):c.2144A>G (p.Lys715Arg)	SLC12A6	Uncertain significance	criteria provided, multiple submitters, no conflicts
2045082	NM_001365088.1(SLC12A6):c.316+3A>G	SLC12A6	Uncertain significance	criteria provided, multiple submitters, no conflicts
2627602	NM_001365088.1(SLC12A6):c.1843G>C (p.Ala615Pro)	SLC12A6	Uncertain significance	criteria provided, single submitter
3577072	NM_001365088.1(SLC12A6):c.703G>C (p.Ala235Pro)	SLC12A6	Uncertain significance	criteria provided, single submitter
4292500	NM_001365088.1(SLC12A6):c.1202T>A (p.Val401Asp)	SLC12A6	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
SLC12A6	Strong	Autosomal dominant	Charcot-Marie-Tooth disease, axonal, IIa 2II	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SLC12A6	Orphanet:1496	Corpus callosum agenesis-neuronopathy syndrome

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SLC12A6	HGNC:10914	ENSG00000140199	Q9UHW9	Solute carrier family 12 member 6	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SLC12A6	Solute carrier family 12 member 6	Mediates electroneutral potassium-chloride cotransport when activated by cell swelling.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SLC12A6	Other/Unknown	no		KCL_cotranspt, AA-permease/SLC12A_dom, SLC12A_fam

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
blood	1
esophagus squamous epithelium	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SLC12A6	274	ubiquitous	marker	esophagus squamous epithelium, blood, secondary oocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SLC12A6	1,463

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SLC12A6	Q9UHW9	8

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective SLC12A6 causes agenesis of the corpus callosum, with peripheral neuropathy (ACCPN)	1	11420.0×	7e-04	SLC12A6
Cation-coupled Chloride cotransporters	1	1631.4×	0.002	SLC12A6
SLC transporter disorders	1	203.9×	0.012	SLC12A6
Disorders of transmembrane transporters	1	139.3×	0.012	SLC12A6
R-HSA-425393	1	129.8×	0.012	SLC12A6
SLC-mediated transmembrane transport	1	59.2×	0.023	SLC12A6
Transport of small molecules	1	25.1×	0.045	SLC12A6
Disease	1	13.1×	0.076	SLC12A6

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
cellular hypotonic salinity response	1	5617.3×	0.002	SLC12A6
chloride ion homeostasis	1	1532.0×	0.003	SLC12A6
cellular hypotonic response	1	1404.3×	0.003	SLC12A6
potassium ion homeostasis	1	766.0×	0.004	SLC12A6
cell volume homeostasis	1	601.9×	0.004	SLC12A6
potassium ion import across plasma membrane	1	366.4×	0.005	SLC12A6
cellular response to glucose stimulus	1	267.5×	0.006	SLC12A6
chloride transmembrane transport	1	237.3×	0.006	SLC12A6
monoatomic ion transport	1	156.0×	0.009	SLC12A6
potassium ion transmembrane transport	1	135.9×	0.009	SLC12A6
chemical synaptic transmission	1	77.3×	0.014	SLC12A6
angiogenesis	1	62.4×	0.016	SLC12A6

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SLC12A6	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	SLC12A6

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
SLC12A6	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.