GeneBe

GLI2

protein-coding

GLI family zinc finger 2, the group of Zinc fingers C2H2-type

Gene summary

This gene encodes a protein which belongs to the C2H2-type zinc finger protein subclass of the Gli family. Members of this subclass are characterized as transcription factors which bind DNA through zinc finger motifs. These motifs contain conserved H-C links. Gli family zinc finger proteins are mediators of Sonic hedgehog (Shh) signaling and they are implicated as potent oncogenes in the embryonal carcinoma cell. The protein encoded by this gene localizes to the cytoplasm and activates patched Drosophila homolog (PTCH) gene expression. It is also thought to play a role during embryogenesis. The encoded protein is associated with several phenotypes- Greig cephalopolysyndactyly syndrome, Pallister-Hall syndrome, preaxial polydactyly type IV, postaxial polydactyly types A1 and B. [provided by RefSeq, Jul 2008]

MANE transcript

NM_001374353.1

Inheritance

AD

ClinVar variants

P:104U:688B:415

Top phenotype

Culler-Jones syndrome

gnomAD constraint

pLI —, LoF o/e 0.18

Max pathogenic AF

—

Genomic locus

chr2:120,735,623-120,992,653

External References & Databases

Ensembl (ENSG00000074047)NCBI Gene (2736)OMIM (165230)HGNC:4318GenCCUniProt (P10070)AlphaFoldClinVar (GLI2)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~257.0 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014369

Submitter: PanelApp Australia

postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014369

Submitter: Labcorp Genetics (formerly Invitae)

postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014369

Submitter: Illumina

holoprosencephaly 9MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0012563

Submitter: Ambry Genetics

postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014369

Submitter: Orphanet

combined pituitary hormone deficiencies, genetic formSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0013099

Submitter: Orphanet

holoprosencephaly 9DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0012563

Submitter: G2P

holoprosencephaly 9STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012563

Submitter: Labcorp Genetics (formerly Invitae)

postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndromeLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0014369

Submitter: Ambry Genetics

postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndromeMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0014369

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Culler-Jones syndromeAD

Manifestation: Craniofacial; Endocrine; Musculoskeletal; Neurologic

Intervention: Endocrine

Rationale: While initially reported (and named) as associated with holoprosencephaly the more classic presentation involves (sometimes subclinical) endocrinological manifestations, including treatable deficiency, such as of thyroid hormone and growth hormone, and awareness may allow endocrine-based testing and management to help amelioriate these manifestations

Refs: 14581620; 15994174; 17096318; 20685856; 22967285; 23112757; 23304807; 23408573; 24744436; 30629636Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to GLI2 variants in ClinVar

56 Conditions Cataloged
Holoprosencephaly 9Total: 672
Postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndromeTotal: 657
not providedTotal: 409
not specifiedTotal: 276
Inborn genetic diseasesTotal: 270
GLI2-related disorderTotal: 223
Microform holoprosencephalyTotal: 6
MicrocephalyTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001374353.1. 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
12
clinvar
283
clinvar
4
clinvar
 299
missense
1
clinvar
6
clinvar
662
clinvar
125
clinvar
2
clinvar
 796
nonsense
14
clinvar
14
clinvar
3
clinvar
 31
start loss
0
frameshift
29
clinvar
32
clinvar
6
clinvar
 67
splice donor/acceptor (+/-2bp)
3
clinvar
5
clinvar
5
clinvar
1
clinvar
 14
Total475768840961207

Highest pathogenic variant AF is 0.000027881524

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 26 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_001374353.1RefSeqNP_001361282.113MANE Select
ENST00000361492.9EnsemblENSP00000354586.513MANE Select
NM_001371271.1RefSeqNP_001358200.113Standard
NM_001374354.1RefSeqNP_001361283.111Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
gli2aDanio rerio

Structure: retinal ganglion cell

Quality: misrouted

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Basal cell carcinoma - Homo sapiens (human)
  • Hippo signaling pathway - Homo sapiens (human)
  • Pathways in cancer - Homo sapiens (human)
  • Hedgehog signaling pathway - Homo sapiens (human)
  • Dopaminergic Neurogenesis

Biological Process

  • negative regulation of transcription by RNA polymerase II
  • skeletal system development
  • in utero embryonic development
  • kidney development
  • chondrocyte differentiation

Molecular Function

  • RNA polymerase II proximal promoter sequence-specific DNA binding
  • DNA-binding transcription factor activity, RNA polymerase II-specific
  • DNA-binding transcription activator activity, RNA polymerase II-specific
  • DNA-binding transcription factor activity
  • protein binding

Cellular Component

  • nucleus
  • nucleoplasm
  • nucleolus
  • cytosol
  • cilium

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000452319
Coding exons
13
Length
257031
Individuals with no LoFs
125718
Homozygous LoFs
0
Heterozygous LoFs
30
Defined
125748
p
0.000119
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense0.8178969670.9260.000066110197
Missense (PolyPhen)326404.350.806224356
Synonymous0.7434284480.9550.00003563362
Loss of Function5.44950.80.1770.00000271531

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000120.00012rare
Latino/Admixed American0.000170.00017rare
Ashkenazi Jewish0.000100.000099rare
East Asian0.000330.00033rare
Finnish00.0absent
European (Non-Finnish)0.0000890.000088rare
South Asian0.000130.00013rare
Other0.000160.00016rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Functions as transcription regulator in the hedgehog (Hh) pathway (PubMed:18455992, PubMed:26565916). Functions as transcriptional activator (PubMed:9557682, PubMed:19878745, PubMed:24311597). May also function as transcriptional repressor (By similarity). Requires STK36 for full transcriptional activator activity. Required for normal embryonic development (PubMed:15994174, PubMed:20685856). {ECO:0000250|UniProtKB:Q0VGT2, ECO:0000269|PubMed:15994174, ECO:0000269|PubMed:18455992, ECO:0000269|PubMed:19878745, ECO:0000269|PubMed:24311597, ECO:0000269|PubMed:26565916, ECO:0000269|PubMed:9557682, ECO:0000305|PubMed:20685856}.; FUNCTION: Isoform 5: Acts as a transcriptional repressor. {ECO:0000269|PubMed:15994174}.;
Disease
DISEASE: Holoprosencephaly 9 (HPE9) [MIM:610829]: A structural anomaly of the brain, in which the developing forebrain fails to correctly separate into right and left hemispheres. Holoprosencephaly is genetically heterogeneous and associated with several distinct facies and phenotypic variability. Holoprosencephaly type 9 is characterized by defective anterior pituitary formation and pan-hypopituitarism, with or without overt forebrain cleavage abnormalities, and holoprosencephaly-like midfacial hypoplasia. {ECO:0000269|PubMed:14581620, ECO:0000269|PubMed:17096318, ECO:0000269|PubMed:20685856}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Culler-Jones syndrome (CJS) [MIM:615849]: An autosomal dominant disorder characterized by a wide range of clinical manifestations. Clinical features include hypothalamic hamartoma, pituitary dysfunction, central or postaxial polydactyly, and syndactyly. Malformations are frequent in the viscera, e.g. anal atresia, bifid uvula, congenital heart malformations, pulmonary or renal dysplasia. {ECO:0000269|PubMed:15994174, ECO:0000269|PubMed:20685856, ECO:0000269|PubMed:23408573}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.341

Intolerance Scores

LoFtool
0.345
RVIS EVS
-1.24
RVIS percentile EVS
5.38

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Indispensability pred.
E
Indispensability score
0.829

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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