FLCN

folliculin, the group of DENN domain containing

Basic information

Region (hg38): 17:17212212-17237188

Links

ENSG00000154803 ∙ NCBI:201163 ∙ OMIM:607273 ∙ HGNC:27310 ∙ Uniprot:Q8NFG4 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Birt-Hogg-Dube syndrome (Strong), mode of inheritance: AD
• renal carcinoma (Strong), mode of inheritance: AD
• familial spontaneous pneumothorax (Strong), mode of inheritance: AD
• Birt-Hogg-Dube syndrome (Strong), mode of inheritance: AD
• familial spontaneous pneumothorax (Moderate), mode of inheritance: AD
• Birt-Hogg-Dube syndrome (Definitive), mode of inheritance: AD
• familial spontaneous pneumothorax (Supportive), mode of inheritance: AD
• Birt-Hogg-Dube syndrome (Supportive), mode of inheritance: AD
• colorectal cancer (Limited), mode of inheritance: AD
• Birt-Hogg-Dube syndrome (Definitive), mode of inheritance: AD
• Birt-Hogg-Dube syndrome (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Birt-Hogg-Dube syndrome 1; Pneumothorax, primary spontaneous	AD	Oncologic; Pulmonary	Individuals are at risk for a number of types of neoplasms, and surveillance and early diagnosis/treatment may be beneficial; Some individuals may demonstrate isolated pneumothorax, but may be at elevated risk for malignancies; Affected individuals commonly have recurrent pneumothoraces, and early pleurodesis may beneficial)	Dermatologic; Oncologic; Pulmonary	596896; 10522666; 11533913; 12471204; 12204536; 15657874; 15852235; 17496196; 18505456; 18234728; 19320655; 20413710; 20618353; 22146830; 23264078; 23414156; 23542717; 23715758; 23846428; 23995526

ClinVar

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

• Birt-Hogg-Dube syndrome (182 variants)
• Hereditary cancer-predisposing syndrome (109 variants)
• not provided (81 variants)
• Birt-Hogg-Dube syndrome 1 (10 variants)
• Familial spontaneous pneumothorax (8 variants)
• FLCN-related disorder (5 variants)
• not specified (3 variants)
• Nonpapillary renal cell carcinoma;Potocki-Lupski syndrome;Familial spontaneous pneumothorax;Colorectal cancer;Birt-Hogg-Dube syndrome (2 variants)
• Carcinoma of colon;Birt-Hogg-Dube syndrome;Potocki-Lupski syndrome;Familial spontaneous pneumothorax;Nonpapillary renal cell carcinoma (1 variants)
• Familial spontaneous pneumothorax;Nonpapillary renal cell carcinoma;Colorectal cancer;Birt-Hogg-Dube syndrome;Potocki-Lupski syndrome (1 variants)
• Potocki-Lupski syndrome (1 variants)
• Colorectal cancer;Familial spontaneous pneumothorax;Nonpapillary renal cell carcinoma;Birt-Hogg-Dube syndrome;Potocki-Lupski syndrome (1 variants)
• Familial spontaneous pneumothorax;Potocki-Lupski syndrome;Colorectal cancer;Nonpapillary renal cell carcinoma;Birt-Hogg-Dube syndrome (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the FLCN 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	10	472	2	485
missense	1	6	815	14	3	839
nonsense	56	7	1	1		65
start loss	5	1				6
frameshift	161	21	2	1		185
inframe indel		6	20			26
splice donor/acceptor (+/-2bp)	13	36	2			51
splice region	2	1	38	59	1	101
non coding			43	197	52	292
Total	236	78	893	685	57

Highest pathogenic variant AF is 0.0000461

Variants in FLCN

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

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

Position	Type	Phenotype	Significance	ClinVar
17-17212252-A-G		Birt-Hogg-Dube syndrome • Familial spontaneous pneumothorax	Benign (Jan 12, 2018)
17-17212319-C-A		Familial spontaneous pneumothorax • Birt-Hogg-Dube syndrome	Benign (Jan 13, 2018)
17-17212382-G-A		Familial spontaneous pneumothorax • Birt-Hogg-Dube syndrome	Uncertain significance (Jan 13, 2018)
17-17212472-C-CT		Birt-Hogg-Dube syndrome • Spontaneous pneumothorax	Benign (Jun 14, 2016)
17-17212475-T-TA		Spontaneous pneumothorax • Birt-Hogg-Dube syndrome	Uncertain significance (Jun 14, 2016)
17-17212476-A-T		Birt-Hogg-Dube syndrome • Familial spontaneous pneumothorax	Uncertain significance (Jan 13, 2018)
17-17212554-G-C		Familial spontaneous pneumothorax • Birt-Hogg-Dube syndrome	Uncertain significance (Jan 12, 2018)
17-17212620-A-G		Familial spontaneous pneumothorax • Birt-Hogg-Dube syndrome	Uncertain significance (Jan 13, 2018)
17-17212688-A-G		Familial spontaneous pneumothorax • Birt-Hogg-Dube syndrome	Uncertain significance (Jan 12, 2018)
17-17212699-T-C		Familial spontaneous pneumothorax • Birt-Hogg-Dube syndrome	Benign (Jan 13, 2018)
17-17212740-C-A		Familial spontaneous pneumothorax • Birt-Hogg-Dube syndrome	Uncertain significance (Jan 12, 2018)
17-17212741-G-A		Familial spontaneous pneumothorax • Birt-Hogg-Dube syndrome	Benign (Jan 13, 2018)
17-17212744-C-T		Familial spontaneous pneumothorax • Birt-Hogg-Dube syndrome	Benign/Likely benign (Jan 12, 2018)
17-17212768-A-G		Familial spontaneous pneumothorax • Birt-Hogg-Dube syndrome	Uncertain significance (Jan 12, 2018)
17-17212809-G-A		Familial spontaneous pneumothorax • Birt-Hogg-Dube syndrome	Uncertain significance (Jan 13, 2018)
17-17212916-G-A		Birt-Hogg-Dube syndrome • Familial spontaneous pneumothorax	Uncertain significance (Jan 13, 2018)
17-17212958-CCG-C		Birt-Hogg-Dube syndrome • Spontaneous pneumothorax	Uncertain significance (Jun 14, 2016)
17-17212960-G-A		Familial spontaneous pneumothorax • Birt-Hogg-Dube syndrome	Conflicting classifications of pathogenicity (May 01, 2023)
17-17213021-T-G		Birt-Hogg-Dube syndrome • Familial spontaneous pneumothorax	Uncertain significance (Jan 12, 2018)
17-17213098-A-G		Birt-Hogg-Dube syndrome • Familial spontaneous pneumothorax	Benign (May 12, 2021)
17-17213127-C-T		Birt-Hogg-Dube syndrome • Familial spontaneous pneumothorax	Conflicting classifications of pathogenicity (Jan 13, 2018)
17-17213129-A-G		Birt-Hogg-Dube syndrome • Familial spontaneous pneumothorax	Benign/Likely benign (Jan 12, 2018)
17-17213213-A-G		Familial spontaneous pneumothorax • Birt-Hogg-Dube syndrome	Benign/Likely benign (May 12, 2021)
17-17213230-C-T		Familial spontaneous pneumothorax • Birt-Hogg-Dube syndrome	Benign (May 12, 2021)
17-17213262-C-T		Birt-Hogg-Dube syndrome • Familial spontaneous pneumothorax	Benign/Likely benign (May 11, 2021)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
FLCN	protein_coding	protein_coding	ENST00000285071	11	24977

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.789	0.211	125723	0	25	125748	0.0000994

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.13	293	353	0.831	0.0000245	3818
Missense in Polyphen		50	81.857	0.61082		910
Synonymous	-0.917	163	149	1.10	0.0000114	1132
Loss of Function	3.94	5	27.1	0.184	0.00000135	293

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000290	0.0000290
Ashkenazi Jewish	0.00	0.00
East Asian	0.000272	0.000272
Finnish	0.00	0.00
European (Non-Finnish)	0.000123	0.000123
Middle Eastern	0.000272	0.000272
South Asian	0.000131	0.000131
Other	0.000163	0.000163

dbNSFP

Source: dbNSFP

• Function: FUNCTION: May be a tumor suppressor. May be involved in energy and/or nutrient sensing through the AMPK and mTOR signaling pathways. May regulate phosphorylation of RPS6KB1. {ECO:0000269|PubMed:12204536, ECO:0000269|PubMed:17028174, ECO:0000269|PubMed:18663353}.
• Disease: DISEASE: Birt-Hogg-Dube syndrome (BHD) [MIM:135150]: A rare autosomal dominant genodermatosis characterized by hair follicle hamartomas (fibrofolliculomas), kidney tumors, and spontaneous pneumothorax. Fibrofolliculomas are part of the triad of Birt- Hogg-Dube syndrome skin lesions that also includes trichodiscomas and acrochordons. Onset of this dermatologic condition is invariably in adulthood. Birt-Hogg-Dube syndrome is associated with a variety of histologic types of renal tumors, including chromophobe renal cell carcinoma (RCC), benign renal oncocytoma, clear-cell RCC and papillary type I RCC. Multiple lipomas, angiolipomas, and parathyroid adenomas are also seen in Birt-Hogg- Dube syndrome patients. {ECO:0000269|PubMed:12204536, ECO:0000269|PubMed:15852235, ECO:0000269|PubMed:18234728, ECO:0000269|PubMed:19785621}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Primary spontaneous pneumothorax (PSP) [MIM:173600]: Condition in which air is present in the pleural space in the absence of a precipitating event, such as trauma or lung disease. This results in secondary collapse of the lung, either partially or completely, and some degree of hypoxia. PSP is relatively common, with an incidence between 7.4-18/100'000 for men and 1.2- 6/100'000 for women and a dose-dependent, increased risk among smokers. Most cases are sporadic, typically occurring in tall, thin men aged 10-30 years and generally while at rest. Familial PSP is rarer and usually is inherited as an autosomal dominant condition with reduced penetrance, although X-linked recessive and autosomal recessive inheritance have also been suggested. {ECO:0000269|PubMed:15657874, ECO:0000269|PubMed:18505456, ECO:0000269|PubMed:18579543}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Renal cell carcinoma (RCC) [MIM:144700]: Renal cell carcinoma is a heterogeneous group of sporadic or hereditary carcinoma derived from cells of the proximal renal tubular epithelium. It is subclassified into clear cell renal carcinoma (non-papillary carcinoma), papillary renal cell carcinoma, chromophobe renal cell carcinoma, collecting duct carcinoma with medullary carcinoma of the kidney, and unclassified renal cell carcinoma. Clear cell renal cell carcinoma is the most common subtype. {ECO:0000269|PubMed:18794106}. Note=The gene represented in this entry may be involved in disease pathogenesis.
• Pathway: mTOR signaling pathway - Homo sapiens (human);Renal cell carcinoma - Homo sapiens (human) (Consensus)

Recessive Scores

• pRec: 0.172

Intolerance Scores

• loftool: 0.0936
• rvis_EVS: -0.2
• rvis_percentile_EVS: 39.17

Haploinsufficiency Scores

• pHI: 0.216
• hipred: Y
• hipred_score: 0.647
• ghis: 0.614

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: S
• essential_gene_gene_trap: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.276

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Flcn
• Phenotype: renal/urinary system phenotype; immune system phenotype; neoplasm; hematopoietic system 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); embryo phenotype; homeostasis/metabolism phenotype; cellular phenotype; growth/size/body region phenotype

Zebrafish Information Network

• Gene name: flcn
• Affected structure: post-vent region
• Phenotype tag: abnormal
• Phenotype quality: bent

Gene ontology

• Biological process: negative regulation of transcription by RNA polymerase II;in utero embryonic development;regulation of protein phosphorylation;positive regulation of protein phosphorylation;cell-cell junction assembly;positive regulation of autophagy;negative regulation of gene expression;negative regulation of mitochondrion organization;hemopoiesis;negative regulation of cell growth;negative regulation of cell migration;positive regulation of transforming growth factor beta receptor signaling pathway;TOR signaling;regulation of TOR signaling;negative regulation of TOR signaling;positive regulation of TOR signaling;regulation of cytokinesis;negative regulation of Rho protein signal transduction;regulation of histone acetylation;positive regulation of apoptotic process;positive regulation of cell adhesion;positive regulation of transcription by RNA polymerase II;negative regulation of protein kinase B signaling;negative regulation of ERK1 and ERK2 cascade;energy homeostasis;negative regulation of cold-induced thermogenesis;negative regulation of protein localization to nucleus;negative regulation of cell proliferation involved in kidney development;regulation of pro-B cell differentiation;negative regulation of ATP biosynthetic process
• Cellular component: nucleus;cytoplasm;lysosome;cytosol;plasma membrane;cilium;midbody;cell-cell contact zone
• Molecular function: guanyl-nucleotide exchange factor activity;protein binding;protein-containing complex binding