rs16989535

Positions:

chr22-31833945-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_001242896.3(DEPDC5):c.2135C>T(p.Ser712Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00611 in 1,610,442 control chromosomes in the GnomAD database, including 256 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.023 ( 115 hom., cov: 32)

Exomes 𝑓: 0.0044 ( 141 hom. )

Consequence

DEPDC5
NM_001242896.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts P:1B:5

Conservation

PhyloP100: 4.70

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:

ENSG00000285404 (HGNC:):

ENSG00000285404 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 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.

BP4

Computational evidence support a benign effect (MetaRNN=0.0021339655).

BP6

Variant 22-31833945-C-T is Benign according to our data. Variant chr22-31833945-C-T is described in ClinVar as [Benign]. Clinvar id is 414462.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31833945-C-T is described in Lovd as [Likely_benign]. Variant chr22-31833945-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0704 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DEPDC5	NM_001242896.3 linkuse as main transcript	c.2135C>T	p.Ser712Phe	missense_variant	25/43	ENST00000651528.2	NP_001229825.1	O75140-10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DEPDC5	ENST00000651528.2 linkuse as main transcript	c.2135C>T	p.Ser712Phe	missense_variant	25/43		NM_001242896.3	ENSP00000498382.1		O75140-10
ENSG00000285404	ENST00000646701.1 linkuse as main transcript	c.1786+14720C>T		intron_variant				ENSP00000496158.1		A0A2R8YF50

Frequencies

GnomAD3 genomes

AF:

0.0226

AC:

3432

AN:

152062

Hom.:

117

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0726

Gnomad AMI

AF:

0.0165

Gnomad AMR

AF:

0.00910

Gnomad ASJ

AF:

0.00374

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0143

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.00228

Gnomad OTH

AF:

0.0148

GnomAD3 exomes

AF:

0.00866

AC:

2139

AN:

247084

Hom.:

AF XY:

0.00793

AC XY:

1063

AN XY:

134068

show subpopulations

Gnomad AFR exome

AF:

0.0754

Gnomad AMR exome

AF:

0.00649

Gnomad ASJ exome

AF:

0.00458

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0133

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00245

Gnomad OTH exome

AF:

0.00503

GnomAD4 exome

AF:

0.00438

AC:

6394

AN:

1458262

Hom.:

141

Cov.:

AF XY:

0.00460

AC XY:

3334

AN XY:

725466

show subpopulations

Gnomad4 AFR exome

AF:

0.0771

Gnomad4 AMR exome

AF:

0.00661

Gnomad4 ASJ exome

AF:

0.00410

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0130

Gnomad4 FIN exome

AF:

0.0000938

Gnomad4 NFE exome

AF:

0.00157

Gnomad4 OTH exome

AF:

0.00724

GnomAD4 genome

AF:

0.0226

AC:

3442

AN:

152180

Hom.:

115

Cov.:

AF XY:

0.0227

AC XY:

1692

AN XY:

74398

show subpopulations

Gnomad4 AFR

AF:

0.0726

Gnomad4 AMR

AF:

0.00909

Gnomad4 ASJ

AF:

0.00374

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0145

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00228

Gnomad4 OTH

AF:

0.0147

Alfa

AF:

0.00561

Hom.:

Bravo

AF:

0.0247

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.00208

AC:

ESP6500AA

AF:

0.0686

AC:

257

ESP6500EA

AF:

0.00268

AC:

ExAC

AF:

0.00955

AC:

1154

Asia WGS

AF:

0.00837

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 27, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Childhood epilepsy with centrotemporal spikes

Pathogenic:1

Pathogenic, no assertion criteria provided

case-control

Bioinformatics Core, Luxembourg Center for Systems Biomedicine

Jan 01, 2017

CAADphred>15 -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Feb 01, 2024

- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 24, 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

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.30

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.030

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

Eigen

Uncertain

0.28

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.96

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

MetaRNN

Benign

0.0021

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

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.4

.;.;.;M;M;.;.;M;M;.;M;.;M;.;M;M;.

PrimateAI

Uncertain

0.48

PROVEAN

Uncertain

-2.9

D;.;.;.;.;.;.;N;N;.;.;.;N;.;N;N;.

REVEL

Benign

0.094

Sift

Uncertain

0.014

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

Sift4G

Uncertain

0.041

D;.;.;.;.;.;.;T;T;.;.;.;T;.;T;T;.

Polyphen

0.96, 0.87

.;.;.;.;D;.;.;P;.;.;.;.;P;.;D;.;.

Vest4

0.59

MVP

0.18

MPC

0.76

ClinPred

0.047

GERP RS

4.4

Varity_R

0.27

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

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