rs16989528

Positions:

chr22-31821553-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.1922C>T(p.Ala641Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0339 in 1,614,110 control chromosomes in the GnomAD database, including 1,125 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.029 ( 99 hom., cov: 32)

Exomes 𝑓: 0.034 ( 1026 hom. )

Consequence

DEPDC5
NM_001242896.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 1.08

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=0.001611352).

BP6

Variant 22-31821553-C-T is Benign according to our data. Variant chr22-31821553-C-T is described in ClinVar as [Benign]. Clinvar id is 257659.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31821553-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0576 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.1922C>T	p.Ala641Val	missense_variant	23/43	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.1922C>T	p.Ala641Val	missense_variant	23/43		NM_001242896.3	ENSP00000498382.1		O75140-10
ENSG00000285404	ENST00000646701.1 linkuse as main transcript	c.1786+2328C>T		intron_variant				ENSP00000496158.1		A0A2R8YF50

Frequencies

GnomAD3 genomes

AF:

0.0285

AC:

4342

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00519

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.0221

Gnomad ASJ

AF:

0.0184

Gnomad EAS

AF:

0.0225

Gnomad SAS

AF:

0.0634

Gnomad FIN

AF:

0.0855

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0342

Gnomad OTH

AF:

0.0311

GnomAD3 exomes

AF:

0.0348

AC:

8664

AN:

249060

Hom.:

224

AF XY:

0.0372

AC XY:

5025

AN XY:

135166

show subpopulations

Gnomad AFR exome

AF:

0.00555

Gnomad AMR exome

AF:

0.0146

Gnomad ASJ exome

AF:

0.0236

Gnomad EAS exome

AF:

0.0201

Gnomad SAS exome

AF:

0.0537

Gnomad FIN exome

AF:

0.0802

Gnomad NFE exome

AF:

0.0346

Gnomad OTH exome

AF:

0.0322

GnomAD4 exome

AF:

0.0344

AC:

50347

AN:

1461812

Hom.:

1026

Cov.:

AF XY:

0.0352

AC XY:

25585

AN XY:

727196

show subpopulations

Gnomad4 AFR exome

AF:

0.00499

Gnomad4 AMR exome

AF:

0.0155

Gnomad4 ASJ exome

AF:

0.0257

Gnomad4 EAS exome

AF:

0.0264

Gnomad4 SAS exome

AF:

0.0562

Gnomad4 FIN exome

AF:

0.0760

Gnomad4 NFE exome

AF:

0.0330

Gnomad4 OTH exome

AF:

0.0336

GnomAD4 genome

AF:

0.0285

AC:

4341

AN:

152298

Hom.:

Cov.:

AF XY:

0.0320

AC XY:

2384

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.00520

Gnomad4 AMR

AF:

0.0221

Gnomad4 ASJ

AF:

0.0184

Gnomad4 EAS

AF:

0.0224

Gnomad4 SAS

AF:

0.0634

Gnomad4 FIN

AF:

0.0855

Gnomad4 NFE

AF:

0.0342

Gnomad4 OTH

AF:

0.0303

Alfa

AF:

0.0312

Hom.:

159

Bravo

AF:

0.0215

TwinsUK

AF:

0.0272

AC:

101

ALSPAC

AF:

0.0265

AC:

102

ESP6500AA

AF:

0.00541

AC:

ESP6500EA

AF:

0.0295

AC:

247

ExAC

AF:

0.0357

AC:

4312

Asia WGS

AF:

0.0360

AC:

128

AN:

3478

EpiCase

AF:

0.0356

EpiControl

AF:

0.0326

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 31, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 26, 2018	- -

not specified

Benign:1

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

May 26, 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

0.11

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.54

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.016

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

Eigen

Benign

-0.42

Eigen_PC

Benign

-0.28

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.91

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

MetaRNN

Benign

0.0016

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

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.5

.;L;L;.;L;L;L;.;L;.;L;L;.

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-1.2

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

REVEL

Benign

0.025

Sift

Benign

0.13

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

Sift4G

Benign

0.33

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

Polyphen

0.061, 0.036

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

Vest4

0.093, 0.17, 0.11, 0.063, 0.10

MPC

0.40

ClinPred

0.011

GERP RS

0.38

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.036

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