rs61731667

Positions:

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2BP6_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. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -15 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), DEPDC5. . Gene score misZ 2.6501 (greater than the threshold 3.09). Trascript score misZ 3.7275 (greater than threshold 3.09). GenCC has associacion of gene with focal epilepsy, Brugada syndrome, epilepsy, familial focal, with variable foci 1, familial focal epilepsy with variable foci, autosomal dominant epilepsy with auditory features, autosomal dominant nocturnal frontal lobe epilepsy.

BP6

Variant 22-31822741-C-A is Benign according to our data. Variant chr22-31822741-C-A is described in ClinVar as [Benign]. Clinvar id is 238674.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31822741-C-A is described in Lovd as [Benign]. Variant chr22-31822741-C-A is described in Lovd as [Likely_benign].

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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 16 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DEPDC5	NM_001242896.3 linkuse as main transcript	c.2055C>A	p.Phe685Leu	missense_variant	24/43	ENST00000651528.2	NP_001229825.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DEPDC5	ENST00000651528.2 linkuse as main transcript	c.2055C>A	p.Phe685Leu	missense_variant	24/43		NM_001242896.3	ENSP00000498382	P4	O75140-10

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

GnomAD3 exomes

AF:

0.0169

AC:

4221

AN:

249294

Hom.:

AF XY:

0.0176

AC XY:

2375

AN XY:

135260

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 SAS exome

AF:

0.0227

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

Gnomad4 AFR exome

AF:

0.00227

Gnomad4 AMR exome

AF:

0.0133

Gnomad4 ASJ exome

AF:

0.00957

Gnomad4 EAS exome

AF:

0.00275

Gnomad4 SAS exome

AF:

0.0224

Gnomad4 FIN exome

AF:

0.0245

Gnomad4 NFE exome

AF:

0.0192

Gnomad4 OTH exome

AF:

0.0168

GnomAD4 genome

AF:

0.0137

AC:

2081

AN:

152276

Hom.:

Cov.:

AF XY:

0.0143

AC XY:

1063

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.00313

Gnomad4 AMR

AF:

0.0145

Gnomad4 ASJ

AF:

0.00807

Gnomad4 EAS

AF:

0.00386

Gnomad4 SAS

AF:

0.0195

Gnomad4 FIN

AF:

0.0246

Gnomad4 NFE

AF:

0.0185

Gnomad4 OTH

AF:

0.0204

Alfa

AF:

0.0173

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

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 07, 2018	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	DEPDC5: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 02, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified

Benign:2

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 27, 2016

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

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

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;.

MutationTaster

Benign

0.62

D;D;D;D;D;D;D;D;D

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over