GeneBe

SLC26A2

protein-coding

solute carrier family 26 member 2, the group of Solute carrier family 26

Gene summary

The diastrophic dysplasia sulfate transporter is a transmembrane glycoprotein implicated in the pathogenesis of several human chondrodysplasias. It apparently is critical in cartilage for sulfation of proteoglycans and matrix organization. [provided by RefSeq, Jul 2008]

Previous symbols:
  • DTD

MANE transcript

NM_000112.4

Inheritance

AR

ClinVar variants

P:259U:266B:294

Top phenotype

Achondrogenesis, type IB; Atelosteogenesis II; De la Chapelle dysplasia; Diastrophic dysplasia; Epiphyseal dysplasia, multiple, 4

gnomAD constraint

pLI —, LoF o/e 0.68

Max pathogenic AF

—

Genomic locus

chr5:149,960,758-149,993,455

External References & Databases

Ensembl (ENSG00000155850)NCBI Gene (1836)OMIM (606718)HGNC:10994GenCCUniProt (P50443)AlphaFoldClinVar (SLC26A2)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~32.7 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

atelosteogenesis type IISUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009727

Submitter: Orphanet

achondrogenesis type IBMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0010966

Submitter: Ambry Genetics

skeletal dysplasiaSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0018230

Submitter: PanelApp Australia

multiple epiphyseal dysplasia type 4DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009189

Submitter: G2P

multiple epiphyseal dysplasia type 4MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0009189

Submitter: Ambry Genetics

diastrophic dysplasiaSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009107

Submitter: Ambry Genetics

achondrogenesis type IBDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010966

Submitter: G2P

SLC26A2-related skeletal dysplasiaDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0100592

Submitter: ClinGen

*SLC26A2* was first associated with autosomal recessive *SLC26A2*-related skeletal dysplasia as early as 1996 (Superti-Furga et al., PMID: 8528239; Hästbacka et al., PMID: 8571951). *SLC26A2* is associated with achondrogenesis type 1B (a fetal/perinatal lethal condition), atelosteogenesis type II, multiple epiphyseal dysplasia (a non-lethal condition), and diastrophic dysplasia depending on level of residual sulfate transport. There is an overlapping phenotypic spectrum with histological and radiographic similarities between clinical presentations. Per criteria outlined by the ClinGen Lumping and Splitting guidelines, the disease entities achondrogenesis type 1B, atelosteogenesis type 2, diastrophic dysplasia, and multiple epiphyseal dysplasia were lumped as a single gene-disease relationship, autosomal recessive *SLC26A2*-related skeletal dysplasia based on similarities in inheritance pattern and phenotype. Evidence supporting this gene-disease relationship includes case-level data and experimental data. At least 15 unique variants (including missense, nonsense, frameshift variants as well as in-frame indels) have been reported in 14 individuals from 8 publications (PMID: 8528239, 8571951, 9637425, 8702490, 8931695, 15316973, 29724173, 30423444). More evidence is available in the literature; however, the maximum score for genetic evidence has been reached. This gene-disease relationship is supported by a knock-out mouse model, a knock-in mouse model, biochemical function, expression studies, and in vitro functional assays (PMID: 30685387, 15703192, 25373420, 25373420, 9575183, 26077908, 11457925, 8931695, 8571951, 8702490). In summary, there is definitive evidence supporting the relationship between *SLC26A2* and autosomal recessive *SLC26A2*-related skeletal dysplasia. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Skeletal Disorders GCEP on the meeting date August 3rd, 2020 (SOP Version 7).

atelosteogenesis type IIMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0009727

Submitter: Ambry Genetics

diastrophic dysplasiaSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009107

Submitter: Labcorp Genetics (formerly Invitae)

SLC26A2-related skeletal dysplasiaDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0100592

Submitter: Natera

multiple epiphyseal dysplasia type 4SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009189

Submitter: Orphanet

achondrogenesis type IBSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010966

Submitter: Orphanet

diastrophic dysplasiaSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009107

Submitter: Orphanet

Clinical Genomic Database (CGD)

Achondrogenesis, type IB; Atelosteogenesis II; De la Chapelle dysplasia; Diastrophic dysplasia; Epiphyseal dysplasia, multiple, 4AR

Manifestation: Craniofacial; Musculoskeletal

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: 13993535; 5703690; 3799721; 4644462; 4064368; 3562108; 8528239; 8571951; 8723083; 8931695; 8723100; 1345170; 7923357; 9108864; 10482955; 10466420; 10465113; 11734236; 11565064; 11303514; 12525546; 12966518; 12220459; 15316973; 18708426; 18925670; 20301483; 20301689; 20525296; 21077202; 21155763; 21922596; 22052783Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SLC26A2 variants in ClinVar

14 Conditions Cataloged
Achondrogenesis, type IBTotal: 712
Diastrophic dysplasiaTotal: 655
Multiple epiphyseal dysplasia type 4Total: 654
Atelosteogenesis type IITotal: 631
not providedTotal: 87
Inborn genetic diseasesTotal: 78
Sulfate transporter-related osteochondrodysplasiaTotal: 48
not specifiedTotal: 32

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000112.4. 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
13
clinvar
274
clinvar
1
clinvar
 288
missense
3
clinvar
40
clinvar
252
clinvar
18
clinvar
1
clinvar
 314
nonsense
16
clinvar
39
clinvar
 55
start loss
2
clinvar
 2
frameshift
54
clinvar
99
clinvar
1
clinvar
 154
splice donor/acceptor (+/-2bp)
2
clinvar
4
clinvar
 6
Total751842662922819

Highest pathogenic variant AF is 0.0014200215

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 27 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_000112.4RefSeqNP_000103.22MANE Select
ENST00000286298.5EnsemblENSP00000286298.42MANE Select
ENST00000433184.1EnsemblENSP00000405496.11Standard
ENST00000503336.1EnsemblENSP00000426053.12Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
slc26a2Danio rerio

Structure: neuromast hair cell

Quality: decreased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Glucocorticoid Receptor Pathway
  • Nuclear Receptors Meta-Pathway
  • Transport and synthesis of PAPS
  • Metabolism of carbohydrates
  • Phase II - Conjugation of compounds

Biological Process

  • ossification
  • ion transport
  • bicarbonate transport
  • oxalate transport
  • 3'-phosphoadenosine 5'-phosphosulfate biosynthetic process

Molecular Function

  • secondary active sulfate transmembrane transporter activity
  • bicarbonate transmembrane transporter activity
  • chloride transmembrane transporter activity
  • sulfate transmembrane transporter activity
  • anion:anion antiporter activity

Cellular Component

  • plasma membrane
  • integral component of plasma membrane
  • membrane
  • apical plasma membrane
  • microvillus membrane

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000286298
Coding exons
2
Length
32719
Individuals with no LoFs
125692
Homozygous LoFs
0
Heterozygous LoFs
53
Defined
125745
p
0.000211
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense0.03143703720.9950.00001844837
Missense (PolyPhen)147141.641.03781857
Synonymous0.4191301360.9540.000006571509
Loss of Function1.231217.60.6838.48e-7272

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000250.00025rare
Latino/Admixed American0.000230.00023rare
Ashkenazi Jewish0.0000990.000099rare
East Asian0.000220.00022rare
Finnish0.0000920.000092rare
European (Non-Finnish)0.000200.00020rare
South Asian0.000330.00033rare
Other0.000160.00016rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Sulfate transporter. May play a role in endochondral bone formation. {ECO:0000269|PubMed:7923357}.;
Disease
DISEASE: Achondrogenesis 1B (ACG1B) [MIM:600972]: A form of achondrogenesis type 1, a lethal form of chondrodysplasia characterized by deficient ossification in the lumbar vertebrae and absent ossification in the sacral, pubic and ischial bones and clinically by stillbirth or early death. In addition to severe micromelia, there is a disproportionately large cranium due to marked edema of soft tissues. ACG1B is an autosomal recessive disease. {ECO:0000269|PubMed:8528239}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Atelosteogenesis 2 (AO2) [MIM:256050]: A perinatal dysplasia characterized by shortening of the limbs, a dysmorphic syndrome and radiographic skeletal features. Patients are stillborn or die soon after birth. {ECO:0000269|PubMed:8571951}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Multiple epiphyseal dysplasia 4 (EDM4) [MIM:226900]: A generalized skeletal dysplasia associated with significant morbidity. Joint pain, joint deformity, waddling gait, and short stature are the main clinical signs and symptoms. Radiological examination of the skeleton shows delayed, irregular mineralization of the epiphyseal ossification centers and of the centers of the carpal and tarsal bones. Multiple epiphyseal dysplasia is broadly categorized into the more severe Fairbank and the milder Ribbing types. The Fairbank type is characterized by shortness of stature, short and stubby fingers, small epiphyses in several joints, including the knee, ankle, hand, and hip. The Ribbing type is confined predominantly to the hip joints and is characterized by hands that are normal and stature that is normal or near-normal. Multiple epiphyseal dysplasia type 4 is a recessively inherited form, characterized by early childhood-onset hip dysplasia and recurrent patella dislocation. Short stature is not frequent. {ECO:0000269|PubMed:12966518, ECO:0000269|PubMed:21922596}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.194

Intolerance Scores

LoFtool
0.202
RVIS EVS
0.18
RVIS percentile EVS
66.17

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
N
Indispensability score
0.152

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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