chr22-31797646-G-T

Position:

chr22-31797646-G-T

Variant summary

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

The NM_001242896.3(DEPDC5):c.814G>T(p.Val272Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,461,822 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V272I) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

DEPDC5
NM_001242896.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 7.89

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 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=0.14174998).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DEPDC5	NM_001242896.3 linkuse as main transcript	c.814G>T	p.Val272Leu	missense_variant	13/43	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.814G>T	p.Val272Leu	missense_variant	13/43		NM_001242896.3	ENSP00000498382.1		O75140-10
ENSG00000285404	ENST00000646701.1 linkuse as main transcript	c.730G>T	p.Val244Leu	missense_variant	11/21			ENSP00000496158.1		A0A2R8YF50

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000161

AC:

AN:

249096

Hom.:

AF XY:

0.0000222

AC XY:

AN XY:

135138

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000186

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000821

AC:

AN:

1461822

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727216

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000899

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

ExAC

AF:

0.000166

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

May 03, 2021

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. Experimental studies have shown that this variant does not substantially affect DEPDC5 protein function (PMID: 25366275). This variant has been observed in individual(s) with clinical features of DEPDC5-related conditions (PMID: 24591017). ClinVar contains an entry for this variant (Variation ID: 264752). This variant is present in population databases (rs187334123, ExAC 0.2%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This sequence change replaces valine with leucine at codon 272 of the DEPDC5 protein (p.Val272Leu). The valine residue is highly conserved and there is a small physicochemical difference between valine and leucine. -

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

Uncertain

0.40

BayesDel_addAF

Uncertain

0.070

BayesDel_noAF

Benign

-0.14

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.25

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

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

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

M_CAP

Benign

0.039

MetaRNN

Benign

0.14

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

MetaSVM

Benign

-0.65

MutationAssessor

Benign

1.7

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

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-1.8

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

REVEL

Benign

0.14

Sift

Benign

0.10

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

Sift4G

Benign

0.14

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

Polyphen

0.57, 1.0

.;.;.;.;.;.;.;P;D;.;.;.;.;.;P;D;.;.;.;.;.;.

Vest4

0.59

MutPred

0.35

Loss of methylation at K276 (P = 0.0882);Loss of methylation at K276 (P = 0.0882);Loss of methylation at K276 (P = 0.0882);Loss of methylation at K276 (P = 0.0882);Loss of methylation at K276 (P = 0.0882);Loss of methylation at K276 (P = 0.0882);.;Loss of methylation at K276 (P = 0.0882);Loss of methylation at K276 (P = 0.0882);.;Loss of methylation at K276 (P = 0.0882);Loss of methylation at K276 (P = 0.0882);Loss of methylation at K276 (P = 0.0882);.;Loss of methylation at K276 (P = 0.0882);Loss of methylation at K276 (P = 0.0882);Loss of methylation at K276 (P = 0.0882);Loss of methylation at K276 (P = 0.0882);Loss of methylation at K276 (P = 0.0882);Loss of methylation at K276 (P = 0.0882);Loss of methylation at K276 (P = 0.0882);.;

MVP

0.31

MPC

1.2

ClinPred

0.39

GERP RS

5.0

Varity_R

0.74

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

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