chr22-31765049-G-A

Position:

chr22-31765049-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_001242896.3(DEPDC5):c.268G>A(p.Val90Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000744 in 1,612,688 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

DEPDC5
NM_001242896.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter P:1U:1O:1

Conservation

PhyloP100: 5.46

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 Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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=0.16031513).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DEPDC5	NM_001242896.3 linkuse as main transcript	c.268G>A	p.Val90Ile	missense_variant	5/43	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.268G>A	p.Val90Ile	missense_variant	5/43		NM_001242896.3	ENSP00000498382	P4	O75140-10

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000160

AC:

AN:

249488

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135356

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000685

AC:

AN:

1460564

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

726634

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000540

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152124

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74306

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000487

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.00000827

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:1Other:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

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 -

Familial focal epilepsy with variable foci

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 10, 2024

This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 90 of the DEPDC5 protein (p.Val90Ile). This variant is present in population databases (rs768456731, gnomAD 0.003%). This missense change has been observed in individual(s) with Rolandic epilepsy (PMID: 24591017). ClinVar contains an entry for this variant (Variation ID: 264750). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this missense change does not substantially affect DEPDC5 function (PMID: 25366275). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Epilepsy, familial focal, with variable foci 1

Other:1

not provided, no classification provided

literature only

GeneReviews

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.44

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Benign

0.042

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

Eigen

Benign

-0.10

Eigen_PC

Benign

0.030

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.91

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

M_CAP

Benign

0.013

MetaRNN

Benign

0.16

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

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.9

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

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D;D;N

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-0.80

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

REVEL

Benign

0.039

Sift

Benign

0.048

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

Sift4G

Benign

0.081

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

Polyphen

0.49, 0.26

.;.;.;.;.;.;.;.;P;B;.;.;.;.;.;P;.;B;.;.;.;.;.;.;.

Vest4

0.35

MutPred

0.45

Gain of catalytic residue at P92 (P = 0.059);Gain of catalytic residue at P92 (P = 0.059);Gain of catalytic residue at P92 (P = 0.059);Gain of catalytic residue at P92 (P = 0.059);Gain of catalytic residue at P92 (P = 0.059);Gain of catalytic residue at P92 (P = 0.059);Gain of catalytic residue at P92 (P = 0.059);Gain of catalytic residue at P92 (P = 0.059);Gain of catalytic residue at P92 (P = 0.059);Gain of catalytic residue at P92 (P = 0.059);Gain of catalytic residue at P92 (P = 0.059);Gain of catalytic residue at P92 (P = 0.059);Gain of catalytic residue at P92 (P = 0.059);Gain of catalytic residue at P92 (P = 0.059);Gain of catalytic residue at P92 (P = 0.059);Gain of catalytic residue at P92 (P = 0.059);Gain of catalytic residue at P92 (P = 0.059);Gain of catalytic residue at P92 (P = 0.059);Gain of catalytic residue at P92 (P = 0.059);Gain of catalytic residue at P92 (P = 0.059);Gain of catalytic residue at P92 (P = 0.059);Gain of catalytic residue at P92 (P = 0.059);Gain of catalytic residue at P92 (P = 0.059);.;Gain of catalytic residue at P92 (P = 0.059);

MVP

0.30

MPC

0.32

ClinPred

0.21

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.11

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