rs61731667

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_001242896.3(DEPDC5):c.2055C>A(p.Phe685Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0179 in 1,614,068 control chromosomes in the GnomAD database, including 288 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

Frequency

Genomes: 𝑓 0.014 ( 16 hom., cov: 32)

Exomes 𝑓: 0.018 ( 272 hom. )

Consequence

DEPDC5
NM_001242896.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 1.55

Publications

12 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: Benign. The variant received -16 ACMG points.

BP6

Variant 22-31822741-C-A is Benign according to our data. Variant chr22-31822741-C-A is described in ClinVar as Benign. ClinVar VariationId is 238674.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0137 (2081/152276) while in subpopulation SAS AF = 0.0195 (94/4822). AF 95% confidence interval is 0.0176. There are 16 homozygotes in GnomAd4. There are 1063 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 2081 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DEPDC5	NM_001242896.3 link	c.2055C>A	p.Phe685Leu	missense_variant	Exon 24 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.2055C>A	p.Phe685Leu	missense_variant	Exon 24 of 43		NM_001242896.3	ENSP00000498382.1		O75140-10
ENSG00000285404	ENST00000646701.1 link	c.1786+3516C>A		intron_variant	Intron 20 of 20			ENSP00000496158.1		A0A2R8YF50

Frequencies

GnomAD3 genomes

AF:

0.0137

AC:

2079

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00314

Gnomad AMI

AF:

0.0197

Gnomad AMR

AF:

0.0145

Gnomad ASJ

AF:

0.00807

Gnomad EAS

AF:

0.00385

Gnomad SAS

AF:

0.0191

Gnomad FIN

AF:

0.0246

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0185

Gnomad OTH

AF:

0.0206

GnomAD2 exomes

AF:

0.0169

AC:

4221

AN:

249294

AF XY:

0.0176

show subpopulations

Gnomad AFR exome

AF:

0.00258

Gnomad AMR exome

AF:

0.0132

Gnomad ASJ exome

AF:

0.0111

Gnomad EAS exome

AF:

0.00401

Gnomad FIN exome

AF:

0.0237

Gnomad NFE exome

AF:

0.0195

Gnomad OTH exome

AF:

0.0215

GnomAD4 exome

AF:

0.0183

AC:

26751

AN:

1461792

Hom.:

272

Cov.:

AF XY:

0.0186

AC XY:

13508

AN XY:

727186

show subpopulations

African (AFR)

AF:

0.00227

AC:

AN:

33480

American (AMR)

AF:

0.0133

AC:

594

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00957

AC:

250

AN:

26134

East Asian (EAS)

AF:

0.00275

AC:

109

AN:

39700

South Asian (SAS)

AF:

0.0224

AC:

1934

AN:

86232

European-Finnish (FIN)

AF:

0.0245

AC:

1307

AN:

53404

Middle Eastern (MID)

AF:

0.0196

AC:

113

AN:

5768

European-Non Finnish (NFE)

AF:

0.0192

AC:

21352

AN:

1111958

Other (OTH)

AF:

0.0168

AC:

1016

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

1377

2754

4130

5507

6884

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

802

1604

2406

3208

4010

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0137

AC:

2081

AN:

152276

Hom.:

Cov.:

AF XY:

0.0143

AC XY:

1063

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.00313

AC:

130

AN:

41572

American (AMR)

AF:

0.0145

AC:

222

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00807

AC:

AN:

3468

East Asian (EAS)

AF:

0.00386

AC:

AN:

5188

South Asian (SAS)

AF:

0.0195

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0246

AC:

261

AN:

10608

Middle Eastern (MID)

AF:

0.0306

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0185

AC:

1256

AN:

68022

Other (OTH)

AF:

0.0204

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

104

208

312

416

520

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

130

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0171

Hom.:

Bravo

AF:

0.0133

TwinsUK

AF:

0.0175

AC:

ALSPAC

AF:

0.0163

AC:

ESP6500AA

AF:

0.00329

AC:

ESP6500EA

AF:

0.0203

AC:

169

ExAC

AF:

0.0165

AC:

1991

Asia WGS

AF:

0.0110

AC:

AN:

3478

EpiCase

AF:

0.0209

EpiControl

AF:

0.0207

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

DEPDC5: BS1, BS2 -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Aug 02, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 07, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Apr 27, 2016

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Familial focal epilepsy with variable foci

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.014

.;.;.;.;T;.;.;.;T;.;.;.;.

Eigen

Benign

0.0088

Eigen_PC

Benign

0.12

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.76

T;T;T;T;T;.;T;T;.;T;.;T;T

MetaRNN

Benign

0.0040

T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.1

.;L;L;.;L;L;L;.;L;.;L;L;.

PhyloP100

1.6

PrimateAI

Uncertain

0.65

PROVEAN

Benign

0.18

.;.;.;.;N;N;.;.;N;.;N;N;.

REVEL

Benign

0.062

Sift

Benign

0.58

.;.;.;.;T;T;.;.;T;.;T;T;.

Sift4G

Benign

0.76

.;.;.;.;T;T;.;.;T;.;T;T;.

Polyphen

0.065, 0.21

.;.;B;.;B;.;.;.;B;.;B;.;.

Vest4

0.35, 0.37, 0.34, 0.25, 0.33

MutPred

0.14

Loss of catalytic residue at F685 (P = 0.0983);Loss of catalytic residue at F685 (P = 0.0983);Loss of catalytic residue at F685 (P = 0.0983);.;Loss of catalytic residue at F685 (P = 0.0983);Loss of catalytic residue at F685 (P = 0.0983);Loss of catalytic residue at F685 (P = 0.0983);.;Loss of catalytic residue at F685 (P = 0.0983);Loss of catalytic residue at F685 (P = 0.0983);Loss of catalytic residue at F685 (P = 0.0983);Loss of catalytic residue at F685 (P = 0.0983);.;

MPC

0.50

ClinPred

0.011

GERP RS

4.3

Varity_R

0.22

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.29

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.29

Position offset: -48

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

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over