rs181347577

chr22-31822706-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001242896.3(DEPDC5):c.2020C>T(p.Arg674Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00252 in 1,614,050 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0021 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0026 (6 hom.)
• Consequence: DEPDC5 NM_001242896.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:11
• Conservation: PhyloP100: 3.73

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, DEPDC5
• BP4: Computational evidence support a benign effect (MetaRNN=0.0063586533).
• BP6: Variant 22-31822706-C-T is Benign according to our data. Variant chr22-31822706-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 238673.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31822706-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00206 (314/152286) while in subpopulation NFE AF= 0.00259 (176/68020). AF 95% confidence interval is 0.00227. There are 2 homozygotes in gnomad4. There are 151 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DEPDC5	NM_001242896.3	c.2020C>T	p.Arg674Cys	missense_variant	24/43	ENST00000651528.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DEPDC5	ENST00000651528.2	c.2020C>T	p.Arg674Cys	missense_variant	24/43		NM_001242896.3	P4

Frequencies

GnomAD3 genomes AF: 0.00206 AC: 314 AN: 152168 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.0318

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00697

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00259

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.00218 AC: 542 AN: 249146 Hom.: 0 AF XY: 0.00200 AC XY: 270 AN XY: 135194

Gnomad AFR exome AF: 0.000323

Gnomad AMR exome AF: 0.000348

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000916

Gnomad FIN exome AF: 0.00659

Gnomad NFE exome AF: 0.00305

Gnomad OTH exome AF: 0.00182

GnomAD4 exome AF: 0.00257 AC: 3760 AN: 1461764 Hom.: 6 Cov.: 30 AF XY: 0.00249 AC XY: 1813 AN XY: 727180

Gnomad4 AFR exome AF: 0.000538

Gnomad4 AMR exome AF: 0.000313

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000928

Gnomad4 FIN exome AF: 0.00693

Gnomad4 NFE exome AF: 0.00285

Gnomad4 OTH exome AF: 0.00180

GnomAD4 genome AF: 0.00206 AC: 314 AN: 152286 Hom.: 2 Cov.: 32 AF XY: 0.00203 AC XY: 151 AN XY: 74454

Gnomad4 AFR AF: 0.000553

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00697

Gnomad4 NFE AF: 0.00259

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.00237 Hom.: 1

Bravo AF: 0.00167

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00285 AC: 11

ESP6500AA AF: 0.000508 AC: 2

ESP6500EA AF: 0.00264 AC: 22

ExAC AF: 0.00244 AC: 295

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00229

EpiControl AF: 0.00184

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1 Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 29, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	DEPDC5: BP4, BS1 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 26, 2018	- -

Epilepsy, familial focal, with variable foci 1 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

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 -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 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

Invitae

Jan 17, 2024

- -

DEPDC5-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 05, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.39
Cadd	Uncertain	25
Dann	Uncertain	1.0
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.88	D;D;D;D;D;.;D;D;.;D;.;D;D
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.0064	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D
PrimateAI	Benign	0.35	T
Polyphen		1.0, 1.0	.;.;D;.;D;.;.;.;D;.;D;.;.
Vest4		0.48, 0.51, 0.43, 0.48, 0.49
MVP		0.11
MPC		1.3
ClinPred		0.037	T
GERP RS		4.3
Varity_R		0.14

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs181347577; hg19: chr22-32218692;