rs61731667

chr22-31822741-C-Achr22-31822741-C-G

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2 BP6_Very_Strong BS1 BS2

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 (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin ClinVar.

• Frequency:
  • Genomes: 𝑓 0.014 (16 hom., cov: 32)
  • Exomes 𝑓: 0.018 (272 hom.)
• Consequence: DEPDC5 NM_001242896.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.55

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 -15 ACMG points.

• PP2: Missense variant where missense usually causes diseases, DEPDC5
• 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 GnomAd at 16 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DEPDC5	NM_001242896.3	c.2055C>A	p.Phe685Leu	missense_variant	24/43	ENST00000651528.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DEPDC5	ENST00000651528.2	c.2055C>A	p.Phe685Leu	missense_variant	24/43		NM_001242896.3	P4

Frequencies

GnomAD3 genomes AF: 0.0137 AC: 2079 AN: 152160 Hom.: 16 Cov.: 32

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.: 38 AF XY: 0.0176 AC XY: 2375 AN XY: 135260

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.: 30 AF XY: 0.0186 AC XY: 13508 AN XY: 727186

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.: 16 Cov.: 32 AF XY: 0.0143 AC XY: 1063 AN XY: 74448

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.: 43

Bravo AF: 0.0133

TwinsUK AF: 0.0175 AC: 65

ALSPAC AF: 0.0163 AC: 63

ESP6500AA AF: 0.00329 AC: 13

ESP6500EA AF: 0.0203 AC: 169

ExAC AF: 0.0165 AC: 1991

Asia WGS AF: 0.0110 AC: 37 AN: 3478

EpiCase AF: 0.0209

EpiControl AF: 0.0207

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 02, 2019	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	DEPDC5: BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 07, 2018	- -

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

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.53
Cadd	Benign	19
Dann	Benign	0.97
Eigen	Benign	0.0088
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.91	D
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	T
MutationTaster	Benign	0.62	D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.65	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	T
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

Other links and lift over

dbSNP: rs61731667; hg19: chr22-32218727; COSMIC: COSV56707650; COSMIC: COSV56707650;