GRHL2

grainyhead like transcription factor 2

Basic information

Region (hg38): 8:101492439-101669726

Previous symbols: [ "DFNA28", "TFCP2L3" ]

Links

ENSG00000083307 ∙ NCBI:79977 ∙ OMIM:608576 ∙ HGNC:2799 ∙ Uniprot:Q6ISB3 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• autosomal dominant nonsyndromic hearing loss 28 (Strong), mode of inheritance: AD
• congenital fibrosis of extraocular muscles (Limited), mode of inheritance: Unknown
• autosomal dominant nonsyndromic hearing loss 28 (Moderate), mode of inheritance: AD
• nail and teeth abnormalities-marginal palmoplantar keratoderma-oral hyperpigmentation syndrome (Moderate), mode of inheritance: AR
• autosomal dominant nonsyndromic hearing loss (Supportive), mode of inheritance: AD
• posterior polymorphous corneal dystrophy (Supportive), mode of inheritance: AD
• nail and teeth abnormalities-marginal palmoplantar keratoderma-oral hyperpigmentation syndrome (Supportive), mode of inheritance: AR
• nail and teeth abnormalities-marginal palmoplantar keratoderma-oral hyperpigmentation syndrome (Strong), mode of inheritance: AR
• autosomal dominant nonsyndromic hearing loss 28 (Strong), mode of inheritance: AD
• nonsyndromic genetic hearing loss (Strong), mode of inheritance: AD
• posterior polymorphous corneal dystrophy (Strong), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Cornealy dystrophy, posterior polymorphous, 4; Ectodermal dysplasia/short stature syndrome	AD/AR	Audiologic/Otolaryngologic; Ophthalmologic	For Corneal dystrophy, posterior polymorphous, 4, individuals may have secondary glaucoma, and awareness may allow surveillance, prompt diagnosis, and management to prevent visual loss; For Ectodermal dysplasia/short stature syndrome, early recognition and treatment of hearing impairment may improve outcomes, including speech and language development	Audiologic/Otolaryngologic; Dental; Dermatologic; Musculoskeletal; Ophthalmologic	12393799; 25152456; 29499165

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the GRHL2 gene.

• not provided (3 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the GRHL2 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			1	24	7	32
missense		1	85	4	2	92
nonsense	2	3				5
start loss						0
frameshift	1	1				2
inframe indel			3			3
splice donor/acceptor (+/-2bp)		6				6
splice region			1	8		9
non coding			4	45	42	91
Total	3	11	93	73	51

Variants in GRHL2

This is a list of pathogenic ClinVar variants found in the GRHL2 region.

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

Position	Type	Phenotype	Significance	ClinVar
8-101492563-C-T			Likely benign (Feb 16, 2019)
8-101492746-C-G		not specified • Corneal dystrophy, posterior polymorphous, 4 • Nail and teeth abnormalities-marginal palmoplantar keratoderma-oral hyperpigmentation syndrome • Autosomal dominant nonsyndromic hearing loss 28	Benign (Aug 10, 2021)
8-101492747-G-C		not specified	Likely benign (Feb 16, 2018)
8-101492766-A-T		not specified	Uncertain significance (Dec 01, 2023)
8-101492921-GA-G		Corneal dystrophy • Corneal dystrophy, posterior polymorphous, 4	Pathogenic/Likely pathogenic (Jan 12, 2022)
8-101493044-CT-C		Corneal dystrophy	Likely pathogenic (Feb 02, 2018)
8-101493333-G-C			Likely benign (Dec 15, 2023)
8-101493333-G-T		Corneal dystrophy • Corneal dystrophy, posterior polymorphous, 4	Pathogenic/Likely pathogenic (Jan 12, 2022)
8-101493429-CCCCTCCCCCGCCT-C			Benign (May 13, 2021)
8-101493463-C-G			Benign (May 12, 2021)
8-101493477-A-G			Benign (May 12, 2021)
8-101493561-C-T			Benign (May 23, 2021)
8-101543073-A-G			Benign (Nov 12, 2018)
8-101543217-C-T			Likely benign (Jun 29, 2018)
8-101543237-A-G			Likely benign (Apr 25, 2023)
8-101543239-A-G		not specified	Conflicting classifications of pathogenicity (May 04, 2022)
8-101543240-G-A		GRHL2-related disorder	Likely pathogenic (Dec 11, 2022)
8-101543246-A-G		not specified	Benign (Jan 29, 2024)
8-101543254-G-T		Progressive sensorineural hearing impairment	Uncertain significance (Sep 03, 2016)
8-101543266-C-T		Inborn genetic diseases	Uncertain significance (Aug 10, 2024)
8-101543270-T-A			Uncertain significance (Feb 17, 2024)
8-101543278-G-A		Inborn genetic diseases	Uncertain significance (Oct 03, 2024)
8-101543289-C-G			Uncertain significance (Sep 26, 2023)
8-101543297-G-A			Uncertain significance (Sep 27, 2022)
8-101543301-A-G			Likely benign (Apr 27, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
GRHL2	protein_coding	protein_coding	ENST00000251808	16	177295

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.997	0.00317	125740	0	8	125748	0.0000318

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.93	246	347	0.709	0.0000205	4174
Missense in Polyphen		67	140.57	0.47664		1771
Synonymous	-1.27	150	131	1.14	0.00000840	1106
Loss of Function	5.04	5	39.0	0.128	0.00000242	435

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000581	0.0000581
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.0000528	0.0000527
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Transcription factor playing an important role in primary neurulation and in epithelial development (PubMed:29309642, PubMed:25152456). Binds directly to the consensus DNA sequence 5'-AACCGGTT-3' acting as an activator and repressor on distinct target genes (By similarity). During embryogenesis, plays unique and cooperative roles with GRHL3 in establishing distinct zones of primary neurulation. Essential for closure 3 (rostral end of the forebrain), functions cooperatively with GRHL3 in closure 2 (forebrain/midbrain boundary) and posterior neuropore closure (By similarity). Regulates epithelial morphogenesis acting as a target gene-associated transcriptional activator of apical junctional complex components. Up-regulates of CLDN3 and CLDN4, as well as of RAB25, which increases the CLDN4 protein and its localization at tight junctions (By similarity). Comprises an essential component of the transcriptional machinery that establishes appropriate expression levels of CLDN4 and CDH1 in different types of epithelia. Exhibits functional redundancy with GRHL3 in epidermal morphogenetic events and epidermal wound repair (By similarity). In lung, forms a regulatory loop with NKX2-1 that coordinates lung epithelial cell morphogenesis and differentiation (By similarity). In keratinocytes, plays a role in telomerase activation during cellular proliferation, regulates TERT expression by binding to TERT promoter region and inhibiting DNA methylation at the 5'-CpG island, possibly by interfering with DNMT1 enzyme activity (PubMed:19015635, PubMed:20938050). In addition, impairs keratinocyte differentiation and epidermal function by inhibiting the expression of genes clustered at the epidermal differentiation complex (EDC) as well as GRHL1 and GRHL3 through epigenetic mechanisms (PubMed:23254293). {ECO:0000250|UniProtKB:Q8K5C0, ECO:0000269|PubMed:19015635, ECO:0000269|PubMed:20938050, ECO:0000269|PubMed:20978075, ECO:0000269|PubMed:23254293, ECO:0000269|PubMed:25152456, ECO:0000269|PubMed:29309642, ECO:0000305|PubMed:12175488}.
• Disease: DISEASE: Deafness, autosomal dominant, 28 (DFNA28) [MIM:608641]: A form of non-syndromic sensorineural hearing loss. Sensorineural deafness results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information. DFNA28 is characterized by mild to moderate hearing loss across most frequencies that progresses to severe loss in the higher frequencies by the fifth decade. {ECO:0000269|PubMed:12393799}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Ectodermal dysplasia/short stature syndrome (ECTDS) [MIM:616029]: An autosomal recessive ectodermal dysplasia syndrome characterized by nail dystrophy and/or loss, oral mucosa and/or tongue pigmentation, abnormal dentition, keratoderma affecting the margins of the palms and soles, focal hyperkeratosis of the dorsal aspects of the hands and feet, and short stature. {ECO:0000269|PubMed:25152456}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Corneal dystrophy, posterior polymorphous, 4 (PPCD4) [MIM:618031]: A subtype of posterior corneal dystrophy, a disease characterized by alterations of Descemet membrane presenting as vesicles, opacities or band-like lesions on slit-lamp examination and specular microscopy. In severe cases, corneal endothelial failure may occur and corneal transplantation is required to restore vision. Secondary complications are common and include corneal edema, glaucoma, iris adherence to the cornea, and corectopia. PPCD4 transmission pattern is consistent with autosomal dominant inheritance. {ECO:0000269|PubMed:29499165}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Mesodermal Commitment Pathway (Consensus)

Recessive Scores

• pRec: 0.152

Intolerance Scores

• loftool: 0.241
• rvis_EVS: -0.4
• rvis_percentile_EVS: 26.73

Haploinsufficiency Scores

• pHI: 0.940
• hipred: Y
• hipred_score: 0.580
• ghis: 0.570

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.460

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Grhl2
• Phenotype: cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); 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); reproductive system phenotype; respiratory system phenotype; embryo phenotype; skeleton phenotype; vision/eye phenotype; limbs/digits/tail 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); growth/size/body region phenotype; craniofacial phenotype

Zebrafish Information Network

• Gene name: grhl2b
• Affected structure: otic epithelium
• Phenotype tag: abnormal
• Phenotype quality: decreased thickness

Gene ontology

• Biological process: neural tube closure;cardiac ventricle morphogenesis;epithelial cell morphogenesis;regulation of transcription by RNA polymerase II;cell adhesion;brain development;cell population proliferation;epidermis development;neural tube development;cell junction assembly;multicellular organism growth;embryonic digit morphogenesis;camera-type eye development;regulation of DNA methylation;negative regulation of keratinocyte differentiation;positive regulation of transcription by RNA polymerase II;embryonic cranial skeleton morphogenesis;positive regulation of telomerase activity;face development;lung lobe morphogenesis;lung epithelial cell differentiation;epithelial cell morphogenesis involved in placental branching;bicellular tight junction assembly;epithelium migration
• Cellular component: nucleus;nucleoplasm;cell-cell junction;membrane
• Molecular function: DNA-binding transcription factor activity, RNA polymerase II-specific;intronic transcription regulatory region sequence-specific DNA binding;DNA-binding transcription activator activity, RNA polymerase II-specific;DNA-binding transcription factor activity;protein binding;chromatin DNA binding;sequence-specific DNA binding