rs61731662

Positions:

chr22-31870617-A-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_001242896.3(DEPDC5):c.3358A>G(p.Met1120Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0218 in 1,576,322 control chromosomes in the GnomAD database, including 439 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.023 ( 40 hom., cov: 33)

Exomes 𝑓: 0.022 ( 399 hom. )

Consequence

DEPDC5
NM_001242896.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.0570

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 -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=0.0023645163).

BP6

Variant 22-31870617-A-G is Benign according to our data. Variant chr22-31870617-A-G is described in ClinVar as [Benign]. Clinvar id is 257661.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31870617-A-G is described in Lovd as [Benign]. Variant chr22-31870617-A-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0233 (3555/152288) while in subpopulation AFR AF= 0.0287 (1194/41556). AF 95% confidence interval is 0.0274. There are 40 homozygotes in gnomad4. There are 1786 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 40 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DEPDC5	NM_001242896.3 linkuse as main transcript	c.3358A>G	p.Met1120Val	missense_variant	34/43	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.3358A>G	p.Met1120Val	missense_variant	34/43		NM_001242896.3	ENSP00000498382	P4	O75140-10

Frequencies

GnomAD3 genomes

AF:

0.0232

AC:

3531

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0283

Gnomad AMI

AF:

0.0197

Gnomad AMR

AF:

0.0219

Gnomad ASJ

AF:

0.00950

Gnomad EAS

AF:

0.00442

Gnomad SAS

AF:

0.0217

Gnomad FIN

AF:

0.0301

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.0213

Gnomad OTH

AF:

0.0330

GnomAD3 exomes

AF:

0.0213

AC:

4638

AN:

217906

Hom.:

AF XY:

0.0218

AC XY:

2585

AN XY:

118700

show subpopulations

Gnomad AFR exome

AF:

0.0279

Gnomad AMR exome

AF:

0.0146

Gnomad ASJ exome

AF:

0.0126

Gnomad EAS exome

AF:

0.00450

Gnomad SAS exome

AF:

0.0272

Gnomad FIN exome

AF:

0.0293

Gnomad NFE exome

AF:

0.0221

Gnomad OTH exome

AF:

0.0251

GnomAD4 exome

AF:

0.0217

AC:

30883

AN:

1424034

Hom.:

399

Cov.:

AF XY:

0.0219

AC XY:

15495

AN XY:

707340

show subpopulations

Gnomad4 AFR exome

AF:

0.0286

Gnomad4 AMR exome

AF:

0.0155

Gnomad4 ASJ exome

AF:

0.0106

Gnomad4 EAS exome

AF:

0.00293

Gnomad4 SAS exome

AF:

0.0265

Gnomad4 FIN exome

AF:

0.0303

Gnomad4 NFE exome

AF:

0.0218

Gnomad4 OTH exome

AF:

0.0218

GnomAD4 genome

AF:

0.0233

AC:

3555

AN:

152288

Hom.:

Cov.:

AF XY:

0.0240

AC XY:

1786

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.0287

Gnomad4 AMR

AF:

0.0219

Gnomad4 ASJ

AF:

0.00950

Gnomad4 EAS

AF:

0.00443

Gnomad4 SAS

AF:

0.0220

Gnomad4 FIN

AF:

0.0301

Gnomad4 NFE

AF:

0.0213

Gnomad4 OTH

AF:

0.0326

Alfa

AF:

0.0220

Hom.:

Bravo

AF:

0.0234

TwinsUK

AF:

0.0205

AC:

ALSPAC

AF:

0.0192

AC:

ESP6500AA

AF:

0.0227

AC:

ESP6500EA

AF:

0.0240

AC:

199

ExAC

AF:

0.0210

AC:

2544

Asia WGS

AF:

0.0170

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

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	GeneDx	Jul 19, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 04, 2018	- -

not specified

Benign:2

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

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 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.049

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.70

CADD

Benign

0.023

DANN

Benign

0.27

DEOGEN2

Benign

0.0098

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

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.0041

LIST_S2

Benign

0.58

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

MetaRNN

Benign

0.0024

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

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.4

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

MutationTaster

Benign

1.0

N;N;N;N;N;N;N;N;N

PrimateAI

Benign

0.27

PROVEAN

Benign

0.18

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

REVEL

Benign

0.024

Sift

Benign

0.89

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

Sift4G

Benign

0.48

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

Polyphen

0.0

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

Vest4

0.049

MPC

0.40

ClinPred

0.0014

GERP RS

-3.2

Varity_R

0.081

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

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