rs587776976

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_001242896.3(DEPDC5):c.715C>T(p.Arg239*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

DEPDC5
NM_001242896.3 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7O:1

Conservation

PhyloP100: 5.70

Publications

8 publications found

Variant links:

Genes affected

DEPDC5 (HGNC:18423): (DEP domain containing 5, GATOR1 subcomplex subunit) This gene encodes a member of the IML1 family of proteins involved in G-protein signaling pathways. The mechanistic target of rapamycin complex 1 (mTORC1) pathway regulates cell growth by sensing the availability of nutrients. The protein encoded by this gene is a component of the GATOR1 (GAP activity toward Rags) complex which inhibits the amino acid-sensing branch of the mTORC1 pathway. Mutations in this gene are associated with autosomal dominant familial focal epilepsy with variable foci. A single nucleotide polymorphism in an intron of this gene has been associated with an increased risk of hepatocellular carcinoma in individuals with chronic hepatitis C virus infection. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2014]

DEPDC5 Gene-Disease associations (from GenCC):

epilepsy, familial focal, with variable foci 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Ambry Genetics, Illumina, G2P
focal epilepsy
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
autosomal dominant epilepsy with auditory features
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
autosomal dominant nocturnal frontal lobe epilepsy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
familial focal epilepsy with variable foci
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Brugada syndrome
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

DEPDC5 links:

ENSG00000285404 (HGNC:):

ENSG00000285404 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 22-31792765-C-T is Pathogenic according to our data. Variant chr22-31792765-C-T is described in CliVar as Pathogenic. Clinvar id is 50824.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31792765-C-T is described in CliVar as Pathogenic. Clinvar id is 50824.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31792765-C-T is described in CliVar as Pathogenic. Clinvar id is 50824.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31792765-C-T is described in CliVar as Pathogenic. Clinvar id is 50824.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31792765-C-T is described in CliVar as Pathogenic. Clinvar id is 50824.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31792765-C-T is described in CliVar as Pathogenic. Clinvar id is 50824.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31792765-C-T is described in CliVar as Pathogenic. Clinvar id is 50824.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31792765-C-T is described in CliVar as Pathogenic. Clinvar id is 50824.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31792765-C-T is described in CliVar as Pathogenic. Clinvar id is 50824.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31792765-C-T is described in CliVar as Pathogenic. Clinvar id is 50824.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31792765-C-T is described in CliVar as Pathogenic. Clinvar id is 50824.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31792765-C-T is described in CliVar as Pathogenic. Clinvar id is 50824.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31792765-C-T is described in CliVar as Pathogenic. Clinvar id is 50824.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31792765-C-T is described in CliVar as Pathogenic. Clinvar id is 50824.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31792765-C-T is described in CliVar as Pathogenic. Clinvar id is 50824.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31792765-C-T is described in CliVar as Pathogenic. Clinvar id is 50824.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31792765-C-T is described in CliVar as Pathogenic. Clinvar id is 50824.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31792765-C-T is described in CliVar as Pathogenic. Clinvar id is 50824.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31792765-C-T is described in CliVar as Pathogenic. Clinvar id is 50824.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31792765-C-T is described in CliVar as Pathogenic. Clinvar id is 50824.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31792765-C-T is described in CliVar as Pathogenic. Clinvar id is 50824.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31792765-C-T is described in CliVar as Pathogenic. Clinvar id is 50824.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31792765-C-T is described in CliVar as Pathogenic. Clinvar id is 50824.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31792765-C-T is described in CliVar as Pathogenic. Clinvar id is 50824.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31792765-C-T is described in CliVar as Pathogenic. Clinvar id is 50824.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31792765-C-T is described in CliVar as Pathogenic. Clinvar id is 50824.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31792765-C-T is described in CliVar as Pathogenic. Clinvar id is 50824.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31792765-C-T is described in CliVar as Pathogenic. Clinvar id is 50824.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31792765-C-T is described in CliVar as Pathogenic. Clinvar id is 50824.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31792765-C-T is described in CliVar as Pathogenic. Clinvar id is 50824.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31792765-C-T is described in CliVar as Pathogenic. Clinvar id is 50824.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31792765-C-T is described in CliVar as Pathogenic. Clinvar id is 50824.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31792765-C-T is described in CliVar as Pathogenic. Clinvar id is 50824.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31792765-C-T is described in CliVar as Pathogenic. Clinvar id is 50824.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31792765-C-T is described in CliVar as Pathogenic. Clinvar id is 50824.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31792765-C-T is described in CliVar as Pathogenic. Clinvar id is 50824.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31792765-C-T is described in CliVar as Pathogenic. Clinvar id is 50824.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31792765-C-T is described in CliVar as Pathogenic. Clinvar id is 50824.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31792765-C-T is described in CliVar as Pathogenic. Clinvar id is 50824.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31792765-C-T is described in CliVar as Pathogenic. Clinvar id is 50824.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31792765-C-T is described in CliVar as Pathogenic. Clinvar id is 50824.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31792765-C-T is described in CliVar as Pathogenic. Clinvar id is 50824.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31792765-C-T is described in CliVar as Pathogenic. Clinvar id is 50824.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31792765-C-T is described in CliVar as Pathogenic. Clinvar id is 50824.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31792765-C-T is described in CliVar as Pathogenic. Clinvar id is 50824.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31792765-C-T is described in CliVar as Pathogenic. Clinvar id is 50824.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31792765-C-T is described in CliVar as Pathogenic. Clinvar id is 50824.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31792765-C-T is described in CliVar as Pathogenic. Clinvar id is 50824.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DEPDC5	NM_001242896.3 link	c.715C>T	p.Arg239*	stop_gained	Exon 12 of 43	ENST00000651528.2	NP_001229825.1	O75140-10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DEPDC5	ENST00000651528.2 link	c.715C>T	p.Arg239*	stop_gained	Exon 12 of 43		NM_001242896.3	ENSP00000498382.1		O75140-10
ENSG00000285404	ENST00000646701.1 link	c.631C>T	p.Arg211*	stop_gained	Exon 10 of 21			ENSP00000496158.1		A0A2R8YF50

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1397056

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

693368

African (AFR)

AF:

0.00

AC:

AN:

28756

American (AMR)

AF:

0.00

AC:

AN:

30046

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24574

East Asian (EAS)

AF:

0.00

AC:

AN:

34688

South Asian (SAS)

AF:

0.00

AC:

AN:

73234

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52824

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5634

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1089558

Other (OTH)

AF:

0.00

AC:

AN:

57742

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Epilepsy, familial focal, with variable foci 1

Pathogenic:2Other:1

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Apr 01, 2015

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PVS1+PM2_Supporting+PS4_Supporting -

not provided

Pathogenic:2

Apr 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

DEPDC5: PVS1, PM2 -

May 29, 2024

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Identified in a patient with focal cortical dysplasia and a family with familial focal epilepsy with variable foci (FFEVF); however, asymptomatic family members also carried the variant, indicating incomplete penetrance (PMID: 23542701, 31444548); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25623524, 30093711, 31444548, 29761115, 32848577, 10825362, 23542697, 34055363, 33461085, 35163267, 37489029, 23542701) -

Seizure

Pathogenic:2

Diagnostic Laboratory, Strasbourg University Hospital

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 27, 2023

Génétique des Maladies du Développement, Hospices Civils de Lyon

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Familial focal epilepsy with variable foci

Pathogenic:1

Apr 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Arg239*) in the DEPDC5 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DEPDC5 are known to be pathogenic (PMID: 23542697, 23542701). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with familial focal epilepsy with variable foci (PMID: 23542701). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 50824). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.63

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Uncertain

0.95

PhyloP100

5.7

Vest4

0.85

GERP RS

5.2

PromoterAI

-0.049

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over