GeneBe

EXT2

protein-coding

exostosin glycosyltransferase 2, the group of Exostosin glycosyltransferase family

Gene summary

This gene encodes one of two glycosyltransferases involved in the chain elongation step of heparan sulfate biosynthesis. Mutations in this gene cause the type II form of multiple exostoses. Alternatively spliced transcript variants encoding different isoforms have been noted for this gene. [provided by RefSeq, Jul 2008]

MANE transcript

NM_207122.2

Inheritance

AR, AD

ClinVar variants

P:247U:403B:224

Top phenotype

Exostoses, multiple, type 2

gnomAD constraint

pLI —, LoF o/e 0.53

Max pathogenic AF

—

Genomic locus

chr11:44,095,648-44,251,962

External References & Databases

Ensembl (ENSG00000151348)NCBI Gene (2132)OMIM (608210)HGNC:3513GenCCUniProt (Q93063)AlphaFoldClinVar (EXT2)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~156.3 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

seizures-scoliosis-macrocephaly syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014731

Submitter: Labcorp Genetics (formerly Invitae)

hereditary multiple osteochondromasSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0005508

Submitter: Orphanet

exostoses, multiple, type 2DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007586

Submitter: Ambry Genetics

seizures-scoliosis-macrocephaly syndromeLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0014731

Submitter: Ambry Genetics

exostoses, multiple, type 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007586

Submitter: Labcorp Genetics (formerly Invitae)

exostoses, multiple, type 2DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007586

Submitter: ClinGen

There is abundant evidence published associating the EXT2 gene with Hereditary Multiple Exostoses (HME) since the gene-disease relationship was first proposed by Stickens et al. (1996). Multiple case level studies have been performed with HME patients that have variants in the EXT2 gene. EXT1 also cause hereditary multiple exostoses and a working model for the formation of exostoses has been proposed to link the heparan sulfate biosynthesis function of EXT2. Multiple mouse and zebra fish models have been established to show the development of osteochondromas and exostoses with EXT2 deficiency. All of these types of evidence are consistent with a definitive relationship between the EXT2 gene and Hereditary Multiple Exostoses (HME).

exostoses, multiple, type 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007586

Submitter: Genomics England PanelApp

exostoses, multiple, type 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007586

Submitter: PanelApp Australia

seizures-scoliosis-macrocephaly syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014731

Submitter: PanelApp Australia

exostoses, multiple, type 2DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007586

Submitter: G2P

seizures-scoliosis-macrocephaly syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014731

Submitter: Orphanet

Clinical Genomic Database (CGD)

Exostoses, multiple, type 2AD

Manifestation: Craniofacial; Gastrointestinal; Genitourinary; Musculoskeletal; Neurologic; Oncologic

Intervention: Oncologic

Rationale: Though data regarding the efficacy of surveillance are lacking, individuals are at risk for the (relatively infrequent) development of malignant change of exostoses, and awareness may allow early detection and management

Comments: Though onset of malignancy is typically described in adulthood, some individuals have been affected at an earlier age; Germline variants have also been implicated in chondrosarcoma

Refs: 7726168; 8782816; 8894688; 9326317; 9463333; 10679937; 11432960; 16879194; 19344451; 20301413; 22258776; 23629877; 23770606; 26246518Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to EXT2 variants in ClinVar

12 Conditions Cataloged
Exostoses, multiple, type 2Total: 843
not providedTotal: 173
Inborn genetic diseasesTotal: 111
not specifiedTotal: 67
EXT2-related disorderTotal: 66
Seizures-scoliosis-macrocephaly syndromeTotal: 64
EXT2-related disordersTotal: 28
Exostoses, multiple, type 1Total: 11

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_207122.2. 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
9
clinvar
160
clinvar
3
clinvar
 173
missense
5
clinvar
11
clinvar
383
clinvar
55
clinvar
6
clinvar
 460
nonsense
53
clinvar
20
clinvar
2
clinvar
 75
start loss
0
frameshift
90
clinvar
21
clinvar
2
clinvar
 113
splice donor/acceptor (+/-2bp)
34
clinvar
12
clinvar
7
clinvar
 53
Total182654032159874

Highest pathogenic variant AF is 0.00005762289

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 52 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_207122.2RefSeqNP_997005.113MANE Select
ENST00000533608.7EnsemblENSP00000431173.213MANE Select
NM_000401.3RefSeqNP_000392.314Standard
NM_001178083.3RefSeqNP_001171554.114Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
ext2Danio rerio

Structure: retinal ganglion cell

Quality: organization quality

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Glycosaminoglycan biosynthesis - heparan sulfate / heparin - Homo sapiens (human)
  • Mesodermal Commitment Pathway
  • Metabolism of carbohydrates
  • HS-GAG biosynthesis
  • Heparan sulfate/heparin (HS-GAG) metabolism

Biological Process

  • ossification
  • mesoderm formation
  • glycosaminoglycan biosynthetic process
  • protein glycosylation
  • signal transduction

Molecular Function

  • protein binding
  • acetylglucosaminyltransferase activity
  • glucuronosyltransferase activity
  • transferase activity, transferring glycosyl groups
  • heparan sulfate N-acetylglucosaminyltransferase activity

Cellular Component

  • Golgi membrane
  • endoplasmic reticulum
  • endoplasmic reticulum membrane
  • Golgi apparatus
  • membrane

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000395673
Coding exons
14
Length
149881
Individuals with no LoFs
125695
Homozygous LoFs
0
Heterozygous LoFs
53
Defined
125748
p
0.000211
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense0.6403944310.9130.00002594918
Missense (PolyPhen)129160.210.805211844
Synonymous-0.2421691651.020.000009811466
Loss of Function2.732139.50.5320.00000216444

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000430.00043rare
Latino/Admixed American0.000260.00026rare
Ashkenazi Jewish00.0absent
East Asian0.000110.00011rare
Finnish0.0000920.000092rare
European (Non-Finnish)0.000190.00019rare
South Asian0.000290.00026rare
Other0.000490.00049rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Glycosyltransferase required for the biosynthesis of heparan-sulfate. The EXT1/EXT2 complex possesses substantially higher glycosyltransferase activity than EXT1 or EXT2 alone. Appears to be a tumor suppressor. Required for the exosomal release of SDCBP, CD63 and syndecan (PubMed:22660413). {ECO:0000269|PubMed:22660413}.;
Disease
DISEASE: Potocki-Shaffer syndrome (POSHS) [MIM:601224]: A syndrome characterized by foramina parietalia permagna, multiple exostoses, and craniofacial dysostosis and mental retardation in some cases. Note=The gene represented in this entry is involved in disease pathogenesis.; DISEASE: Seizures, scoliosis, and macrocephaly syndrome (SSMS) [MIM:616682]: An autosomal recessive syndrome characterized by seizures, intellectual disability, hypotonia, scoliosis, macrocephaly, hypertelorism and renal dysfunction. {ECO:0000269|PubMed:26246518}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.121

Intolerance Scores

LoFtool
0.0377
RVIS EVS
-0.48
RVIS percentile EVS
22.75

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.748

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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