FOXC2

forkhead box C2, the group of Forkhead boxes

Basic information

Region (hg38): 16:86566829-86569728

Previous symbols: [ "FKHL14" ]

Links

ENSG00000176692 ∙ NCBI:2303 ∙ OMIM:602402 ∙ HGNC:3801 ∙ Uniprot:Q99958 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• lymphedema-distichiasis syndrome (Limited), mode of inheritance: AD
• lymphedema-distichiasis syndrome (Definitive), mode of inheritance: AD
• lymphedema-distichiasis syndrome (Strong), mode of inheritance: AD
• lymphedema-distichiasis syndrome (Strong), mode of inheritance: AD
• lymphedema-distichiasis syndrome (Supportive), mode of inheritance: AD
• lymphedema-distichiasis syndrome (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Lymphedema-distichiasis syndrome	AD	Cardiovascular	The condition can involve congenital cardiac anomalies, and awareness may allow early management	Cardiovascular; Dermatologic; Musculoskeletal; Ophthalmologic	14269895; 3573000; 10086462; 11078474; 11499682; 11694548; 12485195; 12114478; 15523639; 17372167; 19760751; 20186799; 20301630; 20450314; 20552815; 21918810; 22349027; 22768468

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the FOXC2 gene.

• not_provided (158 variants)
• Inborn_genetic_diseases (105 variants)
• Distichiasis-lymphedema_syndrome (47 variants)
• FOXC2-related_disorder (14 variants)
• not_specified (12 variants)
• Non-immune_hydrops_fetalis (2 variants)
• LYMPHEDEMA-DISTICHIASIS_SYNDROME_WITH_RENAL_DISEASE_AND_DIABETES_MELLITUS (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the FOXC2 gene is commonly pathogenic or not. These statistics are base on transcript: NM_000005251.3. Only rare variants are included in the table.

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.

Effect	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			12	33	8	53
missense	4	3	160	11		178
nonsense	9	8	2			19
start loss						0
frameshift	25	10	2			37
splice donor/acceptor (+/-2bp)						0
Total	38	21	176	44	8

Highest pathogenic variant AF is 0.000004827412

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
FOXC2	protein_coding	protein_coding	ENST00000320354	1	1683

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
		0	0	0	0	0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-0.251	236	225	1.05	0.0000107	3174
Missense in Polyphen		93	105.96	0.87769		1336
Synonymous	-4.25	159	104	1.53	0.00000534	1042
Loss of Function	2.02	3	9.84	0.305	4.27e-7	131

LoF frequencies by population

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

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Transcriptional activator. Might be involved in the formation of special mesenchymal tissues. {ECO:0000269|PubMed:9169153}.
• Disease: DISEASE: Lymphedema-distichiasis (LYD) [MIM:153400]: A disorder characterized by primary limb lymphedema associated with distichiasis (double rows of eyelashes, with extra eyelashes growing from the Meibomian gland orifices). Swelling of the extremities, due to altered lymphatic flow, usually appears in late childhood or puberty. Most affected individuals have ocular findings including corneal irritation, recurrent conjunctivitis, and photophobia. Drooping of the upper eyelid (ptosis) is a variable feature of the lymphedema-distichiasis syndrome, occurring in about 30% of patients. {ECO:0000269|PubMed:11078474, ECO:0000269|PubMed:11371511, ECO:0000269|PubMed:11499682}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Heart Development;Adipogenesis;Mesodermal Commitment Pathway;BMP Signaling Pathway in Eyelid Development;EMT transition in Colorectal Cancer (Consensus)

Recessive Scores

• pRec: 0.238

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.928

Gene Damage Prediction

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

Gene ontology

• Biological process: negative regulation of transcription by RNA polymerase II;lymphangiogenesis;regulation of transcription by RNA polymerase II;mesoderm development;heart development;insulin receptor signaling pathway;anatomical structure morphogenesis;response to hormone;positive regulation of endothelial cell migration;cell differentiation;positive regulation of cell adhesion mediated by integrin;positive regulation of vascular wound healing;positive regulation of transcription, DNA-templated;positive regulation of transcription by RNA polymerase II;positive regulation of cell migration involved in sprouting angiogenesis;negative regulation of cold-induced thermogenesis
• Cellular component: nucleus;nucleoplasm;nuclear body
• Molecular function: RNA polymerase II regulatory region sequence-specific DNA binding;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;chromatin DNA binding;identical protein binding;sequence-specific DNA binding;transcription regulatory region DNA binding;promoter-specific chromatin binding