rs16989535

chr22-31833945-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_001242896.3(DEPDC5):c.2135C>T(p.Ser712Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00611 in 1,610,442 control chromosomes in the GnomAD database, including 256 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (115 hom., cov: 32)
  • Exomes 𝑓: 0.0044 (141 hom.)
• Consequence: DEPDC5 NM_001242896.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts P:1 B:3
• Conservation: PhyloP100: 4.70

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, DEPDC5
• BP4: Computational evidence support a benign effect (MetaRNN=0.0021339655).
• BP6: Variant 22-31833945-C-T is Benign according to our data. Variant chr22-31833945-C-T is described in ClinVar as [Benign]. Clinvar id is 414462.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31833945-C-T is described in Lovd as [Likely_benign]. Variant chr22-31833945-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0704 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DEPDC5	NM_001242896.3	c.2135C>T	p.Ser712Phe	missense_variant	25/43	ENST00000651528.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DEPDC5	ENST00000651528.2	c.2135C>T	p.Ser712Phe	missense_variant	25/43		NM_001242896.3	P4

Frequencies

GnomAD3 genomes AF: 0.0226 AC: 3432 AN: 152062 Hom.: 117 Cov.: 32

Gnomad AFR AF: 0.0726

Gnomad AMI AF: 0.0165

Gnomad AMR AF: 0.00910

Gnomad ASJ AF: 0.00374

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0143

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00228

Gnomad OTH AF: 0.0148

GnomAD3 exomes AF: 0.00866 AC: 2139 AN: 247084 Hom.: 57 AF XY: 0.00793 AC XY: 1063 AN XY: 134068

Gnomad AFR exome AF: 0.0754

Gnomad AMR exome AF: 0.00649

Gnomad ASJ exome AF: 0.00458

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0133

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00245

Gnomad OTH exome AF: 0.00503

GnomAD4 exome AF: 0.00438 AC: 6394 AN: 1458262 Hom.: 141 Cov.: 30 AF XY: 0.00460 AC XY: 3334 AN XY: 725466

Gnomad4 AFR exome AF: 0.0771

Gnomad4 AMR exome AF: 0.00661

Gnomad4 ASJ exome AF: 0.00410

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0130

Gnomad4 FIN exome AF: 0.0000938

Gnomad4 NFE exome AF: 0.00157

Gnomad4 OTH exome AF: 0.00724

GnomAD4 genome AF: 0.0226 AC: 3442 AN: 152180 Hom.: 115 Cov.: 32 AF XY: 0.0227 AC XY: 1692 AN XY: 74398

Gnomad4 AFR AF: 0.0726

Gnomad4 AMR AF: 0.00909

Gnomad4 ASJ AF: 0.00374

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0145

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00228

Gnomad4 OTH AF: 0.0147

Alfa AF: 0.00561 Hom.: 39

Bravo AF: 0.0247

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.0686 AC: 257

ESP6500EA AF: 0.00268 AC: 22

ExAC AF: 0.00955 AC: 1154

Asia WGS AF: 0.00837 AC: 29 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1 Benign:3

Revision: criteria provided, multiple submitters, no conflicts

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 -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 24, 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

Invitae

Feb 01, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 27, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.30
Cadd	Benign	23
Dann	Uncertain	1.0
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D;D;.;.;D;D;.;D;.;D;D
MetaRNN	Benign	0.0021	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;N;N
PrimateAI	Uncertain	0.48	T
PROVEAN	Uncertain	-2.9	D;.;.;.;.;.;.;N;N;.;.;.;N;.;N;N;.
REVEL	Benign	0.094
Sift	Uncertain	0.014	D;.;.;.;.;.;.;D;D;.;.;.;D;.;D;D;.
Sift4G	Uncertain	0.041	D;.;.;.;.;.;.;T;T;.;.;.;T;.;T;T;.
Polyphen		0.96, 0.87	.;.;.;.;D;.;.;P;.;.;.;.;P;.;D;.;.
Vest4		0.59
MVP		0.18
MPC		0.76
ClinPred		0.047	T
GERP RS		4.4
Varity_R		0.27

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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

Other links and lift over

dbSNP: rs16989535; hg19: chr22-32229931; COSMIC: COSV56708404; COSMIC: COSV56708404;