chr22-31870617-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001242896.3(DEPDC5):c.3358A>G(p.Met1120Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0218 in 1,576,322 control chromosomes in the GnomAD database, including 439 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.023 ( 40 hom., cov: 33)

Exomes 𝑓: 0.022 ( 399 hom. )

Consequence

DEPDC5
NM_001242896.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.0570

Publications

12 publications found

Variant links:

COSMIC-nc: COSV56707734

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0023645163).

BP6

Variant 22-31870617-A-G is Benign according to our data. Variant chr22-31870617-A-G is described in ClinVar as Benign. ClinVar VariationId is 257661.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0233 (3555/152288) while in subpopulation AFR AF = 0.0287 (1194/41556). AF 95% confidence interval is 0.0274. There are 40 homozygotes in GnomAd4. There are 1786 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 3555 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DEPDC5	NM_001242896.3 link	c.3358A>G	p.Met1120Val	missense_variant	Exon 34 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.3358A>G	p.Met1120Val	missense_variant	Exon 34 of 43		NM_001242896.3	ENSP00000498382.1		O75140-10
ENSG00000285404	ENST00000646701.1 link	c.1786+51392A>G		intron_variant	Intron 20 of 20			ENSP00000496158.1		A0A2R8YF50

Frequencies

GnomAD3 genomes

AF:

0.0232

AC:

3531

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0283

Gnomad AMI

AF:

0.0197

Gnomad AMR

AF:

0.0219

Gnomad ASJ

AF:

0.00950

Gnomad EAS

AF:

0.00442

Gnomad SAS

AF:

0.0217

Gnomad FIN

AF:

0.0301

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.0213

Gnomad OTH

AF:

0.0330

GnomAD2 exomes

AF:

0.0213

AC:

4638

AN:

217906

AF XY:

0.0218

show subpopulations

Gnomad AFR exome

AF:

0.0279

Gnomad AMR exome

AF:

0.0146

Gnomad ASJ exome

AF:

0.0126

Gnomad EAS exome

AF:

0.00450

Gnomad FIN exome

AF:

0.0293

Gnomad NFE exome

AF:

0.0221

Gnomad OTH exome

AF:

0.0251

GnomAD4 exome

AF:

0.0217

AC:

30883

AN:

1424034

Hom.:

399

Cov.:

AF XY:

0.0219

AC XY:

15495

AN XY:

707340

show subpopulations

African (AFR)

AF:

0.0286

AC:

905

AN:

31650

American (AMR)

AF:

0.0155

AC:

570

AN:

36880

Ashkenazi Jewish (ASJ)

AF:

0.0106

AC:

260

AN:

24584

East Asian (EAS)

AF:

0.00293

AC:

110

AN:

37566

South Asian (SAS)

AF:

0.0265

AC:

2108

AN:

79640

European-Finnish (FIN)

AF:

0.0303

AC:

1603

AN:

52978

Middle Eastern (MID)

AF:

0.0245

AC:

138

AN:

5632

European-Non Finnish (NFE)

AF:

0.0218

AC:

23912

AN:

1096400

Other (OTH)

AF:

0.0218

AC:

1277

AN:

58704

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

1483

2967

4450

5934

7417

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

916

1832

2748

3664

4580

<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:

0.0233

AC:

3555

AN:

152288

Hom.:

Cov.:

AF XY:

0.0240

AC XY:

1786

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.0287

AC:

1194

AN:

41556

American (AMR)

AF:

0.0219

AC:

334

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00950

AC:

AN:

3472

East Asian (EAS)

AF:

0.00443

AC:

AN:

5188

South Asian (SAS)

AF:

0.0220

AC:

106

AN:

4824

European-Finnish (FIN)

AF:

0.0301

AC:

320

AN:

10616

Middle Eastern (MID)

AF:

0.0340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0213

AC:

1448

AN:

68026

Other (OTH)

AF:

0.0326

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

185

371

556

742

927

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

114

152

190

<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:

0.0218

Hom.:

137

Bravo

AF:

0.0234

TwinsUK

AF:

0.0205

AC:

ALSPAC

AF:

0.0192

AC:

ESP6500AA

AF:

0.0227

AC:

ESP6500EA

AF:

0.0240

AC:

199

ExAC

AF:

0.0210

AC:

2544

Asia WGS

AF:

0.0170

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

May 04, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 19, 2019

GeneDx

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

0.049

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.70

CADD

Benign

0.023

(source)

DANN

Benign

0.27

DEOGEN2

Benign

0.0098

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

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.0041

LIST_S2

Benign

0.58

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

MetaRNN

Benign

0.0024

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

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.4

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

PhyloP100

0.057

PrimateAI

Benign

0.27

PROVEAN

Benign

0.18

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

REVEL

Benign

0.024

Sift

Benign

0.89

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

Sift4G

Benign

0.48

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

Polyphen

0.0

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

Vest4

0.049

MPC

0.40

ClinPred

0.0014

GERP RS

-3.2

Varity_R

0.081

Mutation Taster

=97/3

polymorphism (auto)

(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

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over