Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM2BP4BP6_Very_StrongBS1
The NM_001242896.3(DEPDC5):c.3265-3C>T variant causes a splice region, splice polypyrimidine tract, intron change. The variant allele was found at a frequency of 0.000688 in 1,551,580 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).
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]
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.17).
BP6
Variant 22-31861365-C-T is Benign according to our data. Variant chr22-31861365-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 238679.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31861365-C-T is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00101 (154/152246) while in subpopulation NFE AF= 0.00144 (98/68028). AF 95% confidence interval is 0.00121. There are 0 homozygotes in gnomad4. There are 57 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
This variant is associated with the following publications: (PMID: 29358611, 26505888) -
Likely benign, criteria provided, single submitter
clinical testing
CeGaT Center for Human Genetics Tuebingen
Jul 01, 2024
DEPDC5: BP4 -
Epilepsy, familial focal, with variable foci 1 Benign:1Other:1
Likely benign, criteria provided, single submitter
clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Apr 08, 2022
- -
not provided, no classification provided
literature only
GeneReviews
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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
Likely benign, criteria provided, single submitter
clinical testing
Ambry Genetics
Apr 16, 2018
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. -
Familial focal epilepsy with variable foci Benign:1
Likely benign, criteria provided, single submitter
clinical testing
Invitae
Jan 25, 2024
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DEPDC5-related disorder Benign:1
Benign, criteria provided, single submitter
clinical testing
PreventionGenetics, part of Exact Sciences
Dec 05, 2023
This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -