22-31815018-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001242896.3(DEPDC5):c.1472G>C(p.Ser491Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00661 in 1,614,082 control chromosomes in the GnomAD database, including 682 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S491R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.035 ( 343 hom., cov: 32)

Exomes 𝑓: 0.0036 ( 339 hom. )

Consequence

DEPDC5
NM_001242896.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.124

Publications

10 publications found

Variant links:

COSMIC-nc: COSV56706091

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=0.0012123287).

BP6

Variant 22-31815018-G-C is Benign according to our data. Variant chr22-31815018-G-C is described in ClinVar as Benign. ClinVar VariationId is 414453.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.122 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001242896.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DEPDC5	NM_001242896.3	MANE Select	c.1472G>C	p.Ser491Thr	missense	Exon 21 of 43	NP_001229825.1
DEPDC5	NM_001364318.2		c.1472G>C	p.Ser491Thr	missense	Exon 21 of 43	NP_001351247.1
DEPDC5	NM_001136029.4		c.1472G>C	p.Ser491Thr	missense	Exon 21 of 43	NP_001129501.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DEPDC5	ENST00000651528.2	MANE Select	c.1472G>C	p.Ser491Thr	missense	Exon 21 of 43	ENSP00000498382.1
DEPDC5	ENST00000382112.8	TSL:1	c.1472G>C	p.Ser491Thr	missense	Exon 21 of 43	ENSP00000371546.4
DEPDC5	ENST00000433147.2	TSL:1	c.1388G>C	p.Ser463Thr	missense	Exon 20 of 42	ENSP00000410544.2

Frequencies

GnomAD3 genomes

AF:

0.0353

AC:

5378

AN:

152138

Hom.:

343

Cov.:

show subpopulations

Gnomad AFR

AF:

0.125

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00937

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000827

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000309

Gnomad OTH

AF:

0.0244

GnomAD2 exomes

AF:

0.00867

AC:

2163

AN:

249376

AF XY:

0.00657

show subpopulations

Gnomad AFR exome

AF:

0.128

Gnomad AMR exome

AF:

0.00394

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000159

Gnomad OTH exome

AF:

0.00346

GnomAD4 exome

AF:

0.00362

AC:

5295

AN:

1461826

Hom.:

339

Cov.:

AF XY:

0.00311

AC XY:

2259

AN XY:

727204

show subpopulations

African (AFR)

AF:

0.134

AC:

4487

AN:

33480

American (AMR)

AF:

0.00487

AC:

218

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000301

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00399

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000989

AC:

110

AN:

1111964

Other (OTH)

AF:

0.00714

AC:

431

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

287

574

860

1147

1434

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

134

268

402

536

670

<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:

0.0353

AC:

5382

AN:

152256

Hom.:

343

Cov.:

AF XY:

0.0340

AC XY:

2530

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.124

AC:

5162

AN:

41506

American (AMR)

AF:

0.00935

AC:

143

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.000828

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000309

AC:

AN:

68040

Other (OTH)

AF:

0.0241

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

232

465

697

930

1162

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

168

224

280

<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:

0.00523

Hom.:

Bravo

AF:

0.0404

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.118

AC:

486

ESP6500EA

AF:

0.000357

AC:

ExAC

AF:

0.0109

AC:

1318

Asia WGS

AF:

0.00577

AC:

AN:

3478

EpiCase

AF:

0.000327

EpiControl

AF:

0.000474

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jul 17, 2018

GeneDx

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

Inborn genetic diseases

Benign:1

Jan 08, 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 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.74

BayesDel_noAF

Benign

-0.73

CADD

Benign

0.27

(source)

DANN

Benign

0.67

DEOGEN2

Benign

0.014

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.79

MetaRNN

Benign

0.0012

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-1.4

PhyloP100

-0.12

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.25

REVEL

Benign

0.077

Sift

Benign

0.55

Sift4G

Benign

0.66

Polyphen

0.0

Vest4

0.069

MPC

0.36

ClinPred

0.0039

GERP RS

-12

Varity_R

0.036

Mutation Taster

=100/0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over