GLI2

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

Basic information

Region (hg38): 2:120735622-120992653

Links

ENSG00000074047 ∙ NCBI:2736 ∙ OMIM:165230 ∙ HGNC:4318 ∙ Uniprot:P10070 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• holoprosencephaly 9 (Moderate), mode of inheritance: AD
• postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome (Moderate), mode of inheritance: AD
• postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome (Limited), mode of inheritance: AD
• holoprosencephaly 9 (Definitive), mode of inheritance: AD
• holoprosencephaly (Supportive), mode of inheritance: AR
• combined pituitary hormone deficiencies, genetic form (Supportive), mode of inheritance: AD
• postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome (Supportive), mode of inheritance: AD
• postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome (Definitive), mode of inheritance: AD
• postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome (Strong), mode of inheritance: AD
• holoprosencephaly 9 (Strong), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Culler-Jones syndrome	AD	Endocrine	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	Craniofacial; Endocrine; Musculoskeletal; Neurologic	14581620; 15994174; 17096318; 20685856; 22967285; 23112757; 23304807; 23408573; 24744436; 30629636

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the GLI2 gene.

• not provided (300 variants)
• Holoprosencephaly 9;Postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome (197 variants)
• Holoprosencephaly 9 (158 variants)
• Postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome;Holoprosencephaly 9 (136 variants)
• Inborn genetic diseases (90 variants)
• not specified (88 variants)
• GLI2-related condition (33 variants)
• Postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome (31 variants)
• Holoprosencephaly sequence (16 variants)
• See cases (3 variants)
• Holoprosencephaly 1 (2 variants)
• Pituitary stalk interruption syndrome (2 variants)
• Arteriovenous malformation;Cerebral arteriovenous malformation;Hand tremor;Tremor (1 variants)
• 10 conditions (1 variants)
• Intellectual disability-microcephaly-strabismus-behavioral abnormalities syndrome (1 variants)
• 7 conditions (1 variants)
• GLI2-related disorders (1 variants)
• Developmental disorder (1 variants)
• Bardet-Biedl syndrome (1 variants)
• Microcephaly (1 variants)
• Anophthalmia-microphthalmia syndrome (1 variants)
• Disorder of sexual differentiation (1 variants)
• Cerebellar cyst (1 variants)
• Seizure (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the GLI2 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			14	109	15	138
missense			338	41	9	388
nonsense	8	3				11
start loss						0
frameshift	17	11	3			31
inframe indel		1	6			7
splice donor/acceptor (+/-2bp)	3	1	1			5
splice region			5	9	1	15
non coding		1	29	46	54	130
Total	28	17	391	196	78

Highest pathogenic variant AF is 0.00000657

Variants in GLI2

This is a list of pathogenic ClinVar variants found in the GLI2 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
2-120796980-T-C			Likely benign (Jan 31, 2020)
2-120797077-A-C			Benign (Feb 02, 2019)
2-120797174-A-G			Benign (Apr 24, 2019)
2-120797194-G-T			Likely benign (Nov 09, 2019)
2-120797313-C-T		GLI2-related disorder	Likely benign (Apr 26, 2023)
2-120797314-G-A		not specified • Holoprosencephaly 9 • GLI2-related disorder	Benign/Likely benign (Nov 09, 2019)
2-120797320-G-C		Holoprosencephaly 9	Benign (Jan 12, 2018)
2-120797328-C-T		Postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome;Holoprosencephaly 9 • Inborn genetic diseases	Uncertain significance (Sep 13, 2022)
2-120797328-C-CG		Postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome;Holoprosencephaly 9	Pathogenic (Apr 08, 2022)
2-120797329-G-A		Holoprosencephaly 9;Postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome	Likely benign (Jul 22, 2021)
2-120797350-C-T		Holoprosencephaly 9;Postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome	Likely benign (Dec 18, 2023)
2-120797351-G-A		Holoprosencephaly 9	Uncertain significance (Jan 12, 2018)
2-120797351-G-C		GLI2-related disorder	Uncertain significance (Mar 09, 2023)
2-120797361-A-G			Uncertain significance (Sep 28, 2023)
2-120797365-CA-C		Postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome;Holoprosencephaly 9	Pathogenic (May 06, 2022)
2-120797367-A-G		Inborn genetic diseases	Uncertain significance (Feb 27, 2024)
2-120797376-T-A		Postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome	Uncertain significance (Jul 10, 2020)
2-120797378-C-G		Postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome • Holoprosencephaly 9;Postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome	Uncertain significance (Jan 22, 2022)
2-120797386-C-T		Holoprosencephaly 9;Postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome	Benign (Dec 06, 2023)
2-120797387-G-A		Inborn genetic diseases • GLI2-related disorder	Uncertain significance (Jun 29, 2023)
2-120797391-G-A			Uncertain significance (Nov 10, 2023)
2-120797394-TC-T			Likely pathogenic (Aug 10, 2019)
2-120797395-C-T		Holoprosencephaly 9;Postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome	Likely benign (May 24, 2023)
2-120797398-C-T		Postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome;Holoprosencephaly 9 • GLI2-related disorder	Likely benign (Jan 04, 2024)
2-120797400-ACCCGGGTAAAAAGG-A			Uncertain significance (Jun 10, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
GLI2	protein_coding	protein_coding	ENST00000452319	13	257031

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.973	0.0270	125718	0	30	125748	0.000119

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.817	896	967	0.926	0.0000661	10197
Missense in Polyphen		326	404.35	0.80622		4356
Synonymous	0.743	428	448	0.955	0.0000356	3362
Loss of Function	5.44	9	50.8	0.177	0.00000271	531

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000298	0.000297
Ashkenazi Jewish	0.0000995	0.0000992
East Asian	0.000326	0.000326
Finnish	0.00	0.00
European (Non-Finnish)	0.0000885	0.0000879
Middle Eastern	0.000326	0.000326
South Asian	0.000131	0.000131
Other	0.000163	0.000163

dbNSFP

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.
• Pathway: 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;Hedgehog ,off, state;Tumor suppressor activity of SMARCB1;Hedgehog Signaling Pathway;Hedgehog Signaling Pathway;RUNX2 regulates chondrocyte maturation;RUNX2 regulates bone development;Transcriptional regulation by RUNX2;Signal Transduction;Gene expression (Transcription);Generic Transcription Pathway;Hedgehog;RNA Polymerase II Transcription;Hedgehog;Degradation of GLI2 by the proteasome;Hedgehog ,off, state;GLI proteins bind promoters of Hh responsive genes to promote transcription;Hedgehog ,on, state;Signaling by Hedgehog;Hedgehog signaling events mediated by Gli proteins;Signaling events mediated by the Hedgehog family (Consensus)

Recessive Scores

• pRec: 0.341

Intolerance Scores

• loftool: 0.345
• rvis_EVS: -1.24
• rvis_percentile_EVS: 5.38

Haploinsufficiency Scores

• pHI: 0.978
• hipred: Y
• hipred_score: 0.875
• ghis: 0.526

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.829

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Gli2
• Phenotype: homeostasis/metabolism phenotype; cellular phenotype; muscle phenotype; craniofacial phenotype; growth/size/body region phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); endocrine/exocrine gland phenotype; respiratory system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); skeleton phenotype; digestive/alimentary phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); hearing/vestibular/ear phenotype; limbs/digits/tail phenotype; vision/eye phenotype; reproductive system phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); normal phenotype; embryo phenotype

Zebrafish Information Network

• Gene name: gli2a
• Affected structure: retinal ganglion cell
• Phenotype tag: abnormal
• Phenotype quality: misrouted

Gene ontology

• Biological process: negative regulation of transcription by RNA polymerase II;skeletal system development;in utero embryonic development;kidney development;chondrocyte differentiation;osteoblast development;smoothened signaling pathway;pattern specification process;axon guidance;ventral midline development;hindgut morphogenesis;heart development;cell population proliferation;regulation of smoothened signaling pathway;anterior/posterior pattern specification;proximal/distal pattern formation;floor plate formation;spinal cord dorsal/ventral patterning;ventral spinal cord development;cerebellar cortex morphogenesis;smoothened signaling pathway involved in ventral spinal cord interneuron specification;smoothened signaling pathway involved in spinal cord motor neuron cell fate specification;smoothened signaling pathway involved in regulation of cerebellar granule cell precursor cell proliferation;spinal cord ventral commissure morphogenesis;pituitary gland development;lung development;mammary gland development;hindbrain development;negative regulation of chondrocyte differentiation;positive regulation of T cell differentiation in thymus;tube development;odontogenesis of dentin-containing tooth;embryonic digit morphogenesis;negative regulation of apoptotic process;positive regulation of neuron differentiation;positive regulation of DNA replication;positive regulation of transcription, DNA-templated;positive regulation of transcription by RNA polymerase II;embryonic digestive tract development;developmental growth;neuron development;branching morphogenesis of an epithelial tube;notochord regression;prostatic bud formation;mammary gland duct morphogenesis;smoothened signaling pathway involved in dorsal/ventral neural tube patterning;cellular response to organic cyclic compound;cochlea morphogenesis
• Cellular component: nucleus;nucleoplasm;nucleolus;cytosol;cilium;axoneme;membrane;nuclear speck;motile cilium;ciliary tip;ciliary base
• 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;transcription factor binding;zinc ion binding;sequence-specific DNA binding;promoter-specific chromatin binding