rs146449468

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001242896.3(DEPDC5):c.4512C>T(p.His1504His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0187 in 1,614,118 control chromosomes in the GnomAD database, including 322 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.014 ( 19 hom., cov: 32)

Exomes 𝑓: 0.019 ( 303 hom. )

Consequence

DEPDC5
NM_001242896.3 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.975

Publications

10 publications found

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 Gene-Disease associations (from GenCC):

epilepsy, familial focal, with variable foci 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Ambry Genetics, Illumina, G2P
focal epilepsy
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
autosomal dominant epilepsy with auditory features
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
autosomal dominant nocturnal frontal lobe epilepsy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
familial focal epilepsy with variable foci
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Brugada syndrome
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

DEPDC5 links:

ENSG00000285404 (HGNC:):

ENSG00000285404 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005276859).

BP6

Variant 22-31906059-C-T is Benign according to our data. Variant chr22-31906059-C-T is described in ClinVar as [Benign]. Clinvar id is 238682.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.975 with no splicing effect.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0142 (2164/152310) while in subpopulation SAS AF = 0.0209 (101/4822). AF 95% confidence interval is 0.0183. There are 19 homozygotes in GnomAd4. There are 1106 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 2164 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DEPDC5	NM_001242896.3 link	c.4512C>T	p.His1504His	synonymous_variant	Exon 42 of 43	ENST00000651528.2	NP_001229825.1	O75140-10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DEPDC5	ENST00000651528.2 link	c.4512C>T	p.His1504His	synonymous_variant	Exon 42 of 43		NM_001242896.3	ENSP00000498382.1		O75140-10
ENSG00000285404	ENST00000646701.1 link	c.1787-50080C>T		intron_variant	Intron 20 of 20			ENSP00000496158.1		A0A2R8YF50

Frequencies

GnomAD3 genomes

AF:

0.0142

AC:

2162

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00328

Gnomad AMI

AF:

0.0197

Gnomad AMR

AF:

0.0159

Gnomad ASJ

AF:

0.00806

Gnomad EAS

AF:

0.00250

Gnomad SAS

AF:

0.0205

Gnomad FIN

AF:

0.0250

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0191

Gnomad OTH

AF:

0.0239

GnomAD2 exomes

AF:

0.0177

AC:

4425

AN:

249444

AF XY:

0.0186

show subpopulations

Gnomad AFR exome

AF:

0.00220

Gnomad AMR exome

AF:

0.0140

Gnomad ASJ exome

AF:

0.0110

Gnomad EAS exome

AF:

0.00267

Gnomad FIN exome

AF:

0.0239

Gnomad NFE exome

AF:

0.0203

Gnomad OTH exome

AF:

0.0220

GnomAD4 exome

AF:

0.0192

AC:

28084

AN:

1461808

Hom.:

303

Cov.:

AF XY:

0.0195

AC XY:

14202

AN XY:

727208

show subpopulations

African (AFR)

AF:

0.00230

AC:

AN:

33478

American (AMR)

AF:

0.0139

AC:

620

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00949

AC:

248

AN:

26132

East Asian (EAS)

AF:

0.00214

AC:

AN:

39700

South Asian (SAS)

AF:

0.0254

AC:

2189

AN:

86256

European-Finnish (FIN)

AF:

0.0247

AC:

1318

AN:

53404

Middle Eastern (MID)

AF:

0.0213

AC:

123

AN:

5766

European-Non Finnish (NFE)

AF:

0.0201

AC:

22372

AN:

1111960

Other (OTH)

AF:

0.0174

AC:

1052

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

1442

2885

4327

5770

7212

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0142

AC:

2164

AN:

152310

Hom.:

Cov.:

AF XY:

0.0149

AC XY:

1106

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.00327

AC:

136

AN:

41570

American (AMR)

AF:

0.0159

AC:

243

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00806

AC:

AN:

3472

East Asian (EAS)

AF:

0.00251

AC:

AN:

5180

South Asian (SAS)

AF:

0.0209

AC:

101

AN:

4822

European-Finnish (FIN)

AF:

0.0250

AC:

265

AN:

10620

Middle Eastern (MID)

AF:

0.0306

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0191

AC:

1301

AN:

68034

Other (OTH)

AF:

0.0237

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

107

214

320

427

534

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0185

Hom.:

Bravo

AF:

0.0139

TwinsUK

AF:

0.0183

AC:

ALSPAC

AF:

0.0179

AC:

ESP6500AA

AF:

0.00302

AC:

ESP6500EA

AF:

0.0211

AC:

175

ExAC

AF:

0.0172

AC:

2084

Asia WGS

AF:

0.0120

AC:

AN:

3478

EpiCase

AF:

0.0216

EpiControl

AF:

0.0218

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

May 07, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 02, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Apr 27, 2016

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.49

CADD

Benign

0.55

(source)

DANN

Benign

0.95

Eigen

Benign

-0.78

Eigen_PC

Benign

-0.92

FATHMM_MKL

Benign

0.060

LIST_S2

Benign

0.44

MetaRNN

Benign

0.0053

MetaSVM

Benign

-0.78

PhyloP100

-0.97

PROVEAN

Benign

0.31

REVEL

Benign

0.16

Sift

Benign

0.47

Sift4G

Pathogenic

0.0

Vest4

0.20

ClinPred

0.024

GERP RS

-8.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=98/2

polymorphism (auto)

(source)

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

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rs146449468

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over