22-31821553-C-T

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.1922C>T(p.Ala641Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0339 in 1,614,110 control chromosomes in the GnomAD database, including 1,125 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 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. A641T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.029 ( 99 hom., cov: 32)

Exomes 𝑓: 0.034 ( 1026 hom. )

Consequence

DEPDC5
NM_001242896.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 1.08

Publications

17 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.001611352).

BP6

Variant 22-31821553-C-T is Benign according to our data. Variant chr22-31821553-C-T is described in ClinVar as Benign. ClinVar VariationId is 257659.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0576 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DEPDC5	NM_001242896.3 link	c.1922C>T	p.Ala641Val	missense_variant	Exon 23 of 43	ENST00000651528.2	NP_001229825.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DEPDC5	ENST00000651528.2 link	c.1922C>T	p.Ala641Val	missense_variant	Exon 23 of 43		NM_001242896.3	ENSP00000498382.1
ENSG00000285404	ENST00000646701.1 link	c.1786+2328C>T		intron_variant	Intron 20 of 20			ENSP00000496158.1

Frequencies

GnomAD3 genomes

AF:

0.0285

AC:

4342

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00519

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.0221

Gnomad ASJ

AF:

0.0184

Gnomad EAS

AF:

0.0225

Gnomad SAS

AF:

0.0634

Gnomad FIN

AF:

0.0855

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0342

Gnomad OTH

AF:

0.0311

GnomAD2 exomes

AF:

0.0348

AC:

8664

AN:

249060

AF XY:

0.0372

show subpopulations

Gnomad AFR exome

AF:

0.00555

Gnomad AMR exome

AF:

0.0146

Gnomad ASJ exome

AF:

0.0236

Gnomad EAS exome

AF:

0.0201

Gnomad FIN exome

AF:

0.0802

Gnomad NFE exome

AF:

0.0346

Gnomad OTH exome

AF:

0.0322

GnomAD4 exome

AF:

0.0344

AC:

50347

AN:

1461812

Hom.:

1026

Cov.:

AF XY:

0.0352

AC XY:

25585

AN XY:

727196

show subpopulations

African (AFR)

AF:

0.00499

AC:

167

AN:

33480

American (AMR)

AF:

0.0155

AC:

691

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0257

AC:

673

AN:

26136

East Asian (EAS)

AF:

0.0264

AC:

1047

AN:

39700

South Asian (SAS)

AF:

0.0562

AC:

4843

AN:

86250

European-Finnish (FIN)

AF:

0.0760

AC:

4059

AN:

53412

Middle Eastern (MID)

AF:

0.0342

AC:

197

AN:

5768

European-Non Finnish (NFE)

AF:

0.0330

AC:

36643

AN:

1111950

Other (OTH)

AF:

0.0336

AC:

2027

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.451

Heterozygous variant carriers

2717

5434

8150

10867

13584

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1340

2680

4020

5360

6700

<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:

0.0285

AC:

4341

AN:

152298

Hom.:

Cov.:

AF XY:

0.0320

AC XY:

2384

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.00520

AC:

216

AN:

41574

American (AMR)

AF:

0.0221

AC:

338

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0184

AC:

AN:

3470

East Asian (EAS)

AF:

0.0224

AC:

116

AN:

5186

South Asian (SAS)

AF:

0.0634

AC:

306

AN:

4826

European-Finnish (FIN)

AF:

0.0855

AC:

906

AN:

10598

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0342

AC:

2327

AN:

68026

Other (OTH)

AF:

0.0303

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

212

424

636

848

1060

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

180

240

300

<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:

0.0302

Hom.:

205

Bravo

AF:

0.0215

TwinsUK

AF:

0.0272

AC:

101

ALSPAC

AF:

0.0265

AC:

102

ESP6500AA

AF:

0.00541

AC:

ESP6500EA

AF:

0.0295

AC:

247

ExAC

AF:

0.0357

AC:

4312

Asia WGS

AF:

0.0360

AC:

128

AN:

3478

EpiCase

AF:

0.0356

EpiControl

AF:

0.0326

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Dec 26, 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

- -

Jul 31, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

May 26, 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 02, 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

0.11

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.54

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.016

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

Eigen

Benign

-0.42

Eigen_PC

Benign

-0.28

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.91

D;D;D;D;D;.;D;D;.;D;.;D;D

MetaRNN

Benign

0.0016

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

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.5

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

PhyloP100

1.1

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-1.2

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

REVEL

Benign

0.025

Sift

Benign

0.13

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

Sift4G

Benign

0.33

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

Polyphen

0.061, 0.036

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

Vest4

0.093, 0.17, 0.11, 0.063, 0.10

MPC

0.40

ClinPred

0.011

GERP RS

0.38

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.036

Mutation Taster

=98/2

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