rs886039269

Positions:

• chr22-31879713-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001242896.3(DEPDC5):​c.3994C>T​(p.Arg1332Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,800 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DEPDC5 NM_001242896.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5 O:1
• Conservation: PhyloP100: 7.53

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 Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 22-31879713-C-T is Pathogenic according to our data. Variant chr22-31879713-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 264742.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31879713-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DEPDC5	NM_001242896.3	c.3994C>T	p.Arg1332Ter	stop_gained	38/43	ENST00000651528.2	NP_001229825.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DEPDC5	ENST00000651528.2	c.3994C>T	p.Arg1332Ter	stop_gained	38/43		NM_001242896.3	ENSP00000498382	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461800 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727190

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Epilepsy, familial focal, with variable foci 1 Pathogenic:2 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Oct 02, 2021	Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). It is not observed in the gnomAD v2.1.1 dataset (PM2). The variant has been reported as pathogenic (ClinVar ID: VCV000264742.2).Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Nov 11, 2022	The DEPDC5 c.3994C>T variant is classified as PATHOGENIC (PVS1, PS4) The DEPDC5 c.3994C>T variant is a single nucleotide change which is predicted to result in premature termination of the protein product at codon 1332 (PVS1). The variant has been reported in multiple individuals with focal epilepsy (PMID:30093711; PS4). This variant is absent from population databases but has been reported in dbSNP (rs886039269) and in the HGMD database: CM160826. It has been reported as pathogenic by other diagnostic laboratories (ClinVar Variation ID: 264742). -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 18, 2017

The p.R1332* variant (also known as c.3994C>T), located in coding exon 37 of the DEPDC5 gene, results from a C to T substitution at nucleotide position 3994. This changes the amino acid from an arginine to a stop codon within coding exon 37. In one study, this mutation was detected in an individual with temporal lobe epilepsy and focal cortical dysplasia (Ricos MG et al. Ann. Neurol., 2016 Jan;79:120-31). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

See cases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Mar 02, 2020

ACMG classification criteria: PVS1, PS4, PM2 -

Familial focal epilepsy with variable foci Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 06, 2021

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in DEPDC5 are known to be pathogenic (PMID: 23542697, 23542701). This variant has been observed in individuals with temporal lobe epilepsy and sudden unexpected death in epilepsy as well as one unaffected individual (PMID: 26505888, 26704558). ClinVar contains an entry for this variant (Variation ID: 264742). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Arg1332*) in the DEPDC5 gene. It is expected to result in an absent or disrupted protein product. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	42
DANN	Uncertain	1.0
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.98	D
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A;D
Vest4		0.78
ClinPred		0.99	D
GERP RS		5.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs886039269; hg19: chr22-32275699;