DEPDC5

DEP domain containing 5, GATOR1 subcomplex subunit, the group of GATOR1 subcomplex

Basic information

Region (hg38): 22:31753866-31908033

Links

ENSG00000100150 ∙ NCBI:9681 ∙ OMIM:614191 ∙ HGNC:18423 ∙ Uniprot:O75140 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• epilepsy, familial focal, with variable foci 1 (Definitive), mode of inheritance: AD
• epilepsy, familial focal, with variable foci 1 (Definitive), mode of inheritance: AD
• epilepsy, familial focal, with variable foci 1 (Definitive), mode of inheritance: AD
• autosomal dominant nocturnal frontal lobe epilepsy (Supportive), mode of inheritance: AD
• familial focal epilepsy with variable foci (Supportive), mode of inheritance: AD
• autosomal dominant epilepsy with auditory features (Supportive), mode of inheritance: AD
• Brugada syndrome (Limited), mode of inheritance: AD
• epilepsy, familial focal, with variable foci 1 (Strong), mode of inheritance: AD
• epilepsy, familial focal, with variable foci 1 (Definitive), mode of inheritance: AD
• focal epilepsy (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Developmental and epileptic encephalopathy 111	AR	Allergy/Immunology/Infectious; Cardiovascular	Neutropenia and recurrent infections have been described, and awareness may allow early and aggressive treatment of infections; Developmental and epileptic encephalopathy 111 can include cardiovascular anomalies, and awareness may allow early diagnosis and management	Allergy/Immunology/Infectious; Cardiovascular; Craniofacial; Neurologic; Ophthalmologic	9851433; 10577924; 14510823; 15329069; 22780917; 23542697; 23542701; 24814846; 25623524; 36067010

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the DEPDC5 gene.

• Familial focal epilepsy with variable foci (1539 variants)
• not provided (549 variants)
• Inborn genetic diseases (201 variants)
• Epilepsy, familial focal, with variable foci 1 (175 variants)
• not specified (35 variants)
• DEPDC5-related condition (16 variants)
• Childhood epilepsy with centrotemporal spikes (8 variants)
• Seizure (8 variants)
• See cases (7 variants)
• Intellectual disability (5 variants)
• Developmental and epileptic encephalopathy 111 (2 variants)
• Autosomal dominant nocturnal frontal lobe epilepsy (2 variants)
• DEPDC5-Related Disorder (2 variants)
• SUDDEN INFANT DEATH SYNDROME (2 variants)
• Epileptic encephalopathy (1 variants)
• 10 conditions (1 variants)
• Epilepsy (1 variants)
• Autosomal dominant nocturnal frontal lobe epilepsy;Familial focal epilepsy with variable foci (1 variants)
• Developmental disorder (1 variants)
• DEPDC5-related related disorder (1 variants)
• Continuous spike and waves during slow sleep (1 variants)
• Developmental and epileptic encephalopathy, 83 (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the DEPDC5 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			7	297	12	316
missense		5	781	16	8	810
nonsense	73	13				86
start loss			1			1
frameshift	91	24	9			124
inframe indel	1	1	12			14
splice donor/acceptor (+/-2bp)	14	48	2		1	65
splice region		4	57	60	7	128
non coding			17	258	100	375
Total	179	91	829	571	121

Highest pathogenic variant AF is 0.0000132

Variants in DEPDC5

This is a list of pathogenic ClinVar variants found in the DEPDC5 region.

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

Position	Type	Phenotype	Significance	ClinVar
22-31754865-G-C		Childhood epilepsy with centrotemporal spikes	Pathogenic (Jan 01, 2017)
22-31754922-A-G		Familial focal epilepsy with variable foci	Uncertain significance (Aug 07, 2023)
22-31754926-G-A		Familial focal epilepsy with variable foci • not specified • Inborn genetic diseases	Conflicting classifications of pathogenicity (Oct 04, 2023)
22-31754926-GAAC-G		Familial focal epilepsy with variable foci	Uncertain significance (Aug 27, 2020)
22-31754935-A-G		Familial focal epilepsy with variable foci	Uncertain significance (Dec 21, 2021)
22-31754939-C-T		Familial focal epilepsy with variable foci	Uncertain significance (Oct 07, 2023)
22-31754941-A-G		Familial focal epilepsy with variable foci • Inborn genetic diseases	Uncertain significance (Aug 27, 2023)
22-31754942-C-G		Epilepsy, familial focal, with variable foci 1 • Familial focal epilepsy with variable foci • Inborn genetic diseases	Pathogenic (Jun 14, 2023)
22-31754949-G-A		Familial focal epilepsy with variable foci	Uncertain significance (Jul 17, 2023)
22-31754963-G-A		Familial focal epilepsy with variable foci	Likely benign (Apr 17, 2023)
22-31754966-C-T		Familial focal epilepsy with variable foci • Inborn genetic diseases	Likely benign (Nov 18, 2023)
22-31754971-G-T			Uncertain significance (Mar 28, 2022)
22-31754977-G-C		Epilepsy, familial focal, with variable foci 1	not provided (-)
22-31754980-G-A		Familial focal epilepsy with variable foci	Likely pathogenic (Oct 01, 2022)
22-31754981-T-C		Familial focal epilepsy with variable foci	Likely pathogenic (Dec 11, 2023)
22-31754984-G-C			Likely pathogenic (Apr 29, 2016)
22-31754985-T-C		Familial focal epilepsy with variable foci	Uncertain significance (Feb 03, 2020)
22-31754988-C-T		Familial focal epilepsy with variable foci	Likely benign (Jan 22, 2024)
22-31754989-G-A		Familial focal epilepsy with variable foci	Likely benign (Sep 20, 2023)
22-31754989-G-C		Familial focal epilepsy with variable foci	Likely benign (Dec 30, 2022)
22-31754989-G-T		Familial focal epilepsy with variable foci	Likely benign (Jun 01, 2022)
22-31754994-G-A		Familial focal epilepsy with variable foci	Likely benign (Oct 03, 2023)
22-31754996-C-T		Familial focal epilepsy with variable foci	Likely benign (Jul 30, 2021)
22-31755127-A-G			Likely benign (Jul 26, 2018)
22-31755156-A-G			Likely benign (Jul 31, 2018)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
DEPDC5	protein_coding	protein_coding	ENST00000382112	42	153069

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.117	0.883	124867	0	43	124910	0.000172

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.65	713	942	0.757	0.0000568	10514
Missense in Polyphen		258	395.16	0.65289		4348
Synonymous	0.835	338	358	0.944	0.0000225	3024
Loss of Function	7.15	24	102	0.235	0.00000600	1045

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000595	0.000529
Ashkenazi Jewish	0.0000993	0.0000993
East Asian	0.000285	0.000277
Finnish	0.000279	0.000278
European (Non-Finnish)	0.000125	0.000123
Middle Eastern	0.000285	0.000277
South Asian	0.000164	0.000163
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: As a component of the GATOR1 complex functions as an inhibitor of the amino acid-sensing branch of the TORC1 pathway. The GATOR1 complex strongly increases GTP hydrolysis by RRAGA and RRAGB within RRAGC-containing heterodimers, thereby deactivating RRAGs, releasing mTORC1 from lysosomal surface and inhibiting mTORC1 signaling. The GATOR1 complex is negatively regulated by GATOR2 the other GATOR subcomplex in this amino acid-sensing branch of the TORC1 pathway. {ECO:0000269|PubMed:23723238, ECO:0000269|PubMed:25457612, ECO:0000269|PubMed:29769719}.
• Disease: DISEASE: Epilepsy, familial focal, with variable foci 1 (FFEVF1) [MIM:604364]: An autosomal dominant form of epilepsy characterized by focal seizures arising from different cortical regions in different family members. Many patients have an aura and show automatisms during the seizures, whereas others may have nocturnal seizures. There is often secondary generalization. Some patients show abnormal interictal EEG, and some patients may have intellectual disability or autism spectrum disorders. Seizure onset usually occurs in the first or second decades, although later onset has been reported, and there is phenotypic variability within families. Penetrance of the disorder is incomplete. {ECO:0000269|PubMed:23542697, ECO:0000269|PubMed:23542701, ECO:0000269|PubMed:24283814, ECO:0000269|PubMed:24591017, ECO:0000269|PubMed:25366275, ECO:0000269|PubMed:26505888, ECO:0000269|PubMed:27173016}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Note=Inactivating mutations and truncating deletions in the genes encoding GATOR1 proteins, including DEPDC5, are detected in glioblastoma and ovarian tumors and are associated with loss of heterozygosity events. Inactivation of GATOR1 proteins promotes constitutive localization of mTORC1 to the lysosomal membrane and blocks mTORC1 inactivation following amino acid withdrawal (PubMed:23723238). {ECO:0000269|PubMed:23723238}.
• Pathway: mTOR signaling pathway - Homo sapiens (human) (Consensus)

Recessive Scores

• pRec: 0.0928

Intolerance Scores

• loftool: 0.494
• rvis_EVS: -1.12
• rvis_percentile_EVS: 6.62

Haploinsufficiency Scores

• pHI: 0.194
• hipred: Y
• hipred_score: 0.597
• ghis: 0.544

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.479

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Depdc5
• Phenotype: skeleton 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); 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); behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); homeostasis/metabolism phenotype; growth/size/body region phenotype

Zebrafish Information Network

• Gene name: depdc5
• Affected structure: whole organism
• Phenotype tag: abnormal
• Phenotype quality: increased behavioural activity

Gene ontology

• Biological process: negative regulation of TOR signaling;cellular response to amino acid starvation;intracellular signal transduction;positive regulation of GTPase activity;negative regulation of TORC1 signaling
• Cellular component: lysosome;lysosomal membrane;cytosol;Cul3-RING ubiquitin ligase complex;perinuclear region of cytoplasm;GATOR1 complex
• Molecular function: GTPase activator activity;protein-containing complex binding