rs756142773

Positions:

chr22-31754926-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 3P and 3B. PM2PP2BP4_ModerateBP6

The NM_001242896.3(DEPDC5):c.5G>A(p.Arg2Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000217 in 1,614,206 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

DEPDC5
NM_001242896.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: 3.12

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 0 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=0.11839023).

BP6

Variant 22-31754926-G-A is Benign according to our data. Variant chr22-31754926-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 407350.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DEPDC5	NM_001242896.3 linkuse as main transcript	c.5G>A	p.Arg2Lys	missense_variant	2/43	ENST00000651528.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DEPDC5	ENST00000651528.2 linkuse as main transcript	c.5G>A	p.Arg2Lys	missense_variant	2/43		NM_001242896.3	P4	O75140-10

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000361

AC:

AN:

249574

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135400

show subpopulations

Gnomad AFR exome

AF:

0.0000646

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.0000178

AC:

AN:

1461886

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000201

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000989

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152320

Hom.:

Cov.:

AF XY:

0.0000805

AC XY:

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000392

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000130

Hom.:

Bravo

AF:

0.000144

ExAC

AF:

0.0000331

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Mar 22, 2019

Variant summary: DEPDC5 c.5G>A (p.Arg2Lys) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 277212 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in DEPDC5 causing Epilepsy, familial focal, with variable foci 1 (3.6e-05 vs ND), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.5G>A in individuals affected with Epilepsy, familial focal, with variable foci 1 and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Familial focal epilepsy with variable foci

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 04, 2023

This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 2 of the DEPDC5 protein (p.Arg2Lys). This variant is present in population databases (rs756142773, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with DEPDC5-related conditions. ClinVar contains an entry for this variant (Variation ID: 407350). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Not Available"; Align-GVGD: "Not Available". The lysine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 23, 2023

This alteration is classified as likely 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. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 21, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.49

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.012

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

Eigen

Benign

-0.31

Eigen_PC

Benign

-0.040

FATHMM_MKL

Benign

0.68

LIST_S2

Benign

0.79

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

M_CAP

Benign

0.012

MetaRNN

Benign

0.12

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

-0.89

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

MutationTaster

Benign

1.0

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

PrimateAI

Pathogenic

0.79

PROVEAN

Benign

-0.18

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

REVEL

Benign

0.097

Sift

Benign

0.29

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

Sift4G

Benign

0.39

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

Polyphen

0.0, 0.0010

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

Vest4

0.17

MutPred

0.27

Gain of methylation at R2 (P = 0.0364);Gain of methylation at R2 (P = 0.0364);Gain of methylation at R2 (P = 0.0364);Gain of methylation at R2 (P = 0.0364);Gain of methylation at R2 (P = 0.0364);Gain of methylation at R2 (P = 0.0364);Gain of methylation at R2 (P = 0.0364);Gain of methylation at R2 (P = 0.0364);Gain of methylation at R2 (P = 0.0364);Gain of methylation at R2 (P = 0.0364);Gain of methylation at R2 (P = 0.0364);Gain of methylation at R2 (P = 0.0364);Gain of methylation at R2 (P = 0.0364);Gain of methylation at R2 (P = 0.0364);Gain of methylation at R2 (P = 0.0364);Gain of methylation at R2 (P = 0.0364);Gain of methylation at R2 (P = 0.0364);Gain of methylation at R2 (P = 0.0364);Gain of methylation at R2 (P = 0.0364);Gain of methylation at R2 (P = 0.0364);Gain of methylation at R2 (P = 0.0364);Gain of methylation at R2 (P = 0.0364);Gain of methylation at R2 (P = 0.0364);Gain of methylation at R2 (P = 0.0364);

MVP

0.14

MPC

0.40

ClinPred

0.055

GERP RS

5.3

Varity_R

0.49

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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