rs370940232
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 3P and 3B. PM2PP2BP4_ModerateBP6
The NM_001242896.3(DEPDC5):āc.2066A>Cā(p.Glu689Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000126 in 1,614,016 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: š 0.00011 ( 0 hom., cov: 32)
Exomes š: 0.00013 ( 0 hom. )
Consequence
DEPDC5
NM_001242896.3 missense
NM_001242896.3 missense
Scores
1
5
7
Clinical Significance
Conservation
PhyloP100: 4.56
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]
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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 where missense usually causes diseases, DEPDC5
BP4
?
Computational evidence support a benign effect (MetaRNN=0.14063841).
BP6
?
Variant 22-31822752-A-C is Benign according to our data. Variant chr22-31822752-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 433142.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DEPDC5 | NM_001242896.3 | c.2066A>C | p.Glu689Ala | missense_variant | 24/43 | ENST00000651528.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DEPDC5 | ENST00000651528.2 | c.2066A>C | p.Glu689Ala | missense_variant | 24/43 | NM_001242896.3 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.000105 AC: 16AN: 152188Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000923 AC: 23AN: 249278Hom.: 0 AF XY: 0.0000739 AC XY: 10AN XY: 135256
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GnomAD4 exome AF: 0.000129 AC: 188AN: 1461828Hom.: 0 Cov.: 30 AF XY: 0.000118 AC XY: 86AN XY: 727210
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GnomAD4 genome ? AF: 0.000105 AC: 16AN: 152188Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6AN XY: 74344
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:3Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
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 - |
Epilepsy, familial focal, with variable foci 1 Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics Laboratory, University Hospital Schleswig-Holstein | Nov 21, 2022 | - - |
Familial focal epilepsy with variable foci Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 16, 2023 | This sequence change replaces glutamic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 689 of the DEPDC5 protein (p.Glu689Ala). This variant is present in population databases (rs370940232, gnomAD 0.02%). This missense change has been observed in individual(s) with Rolandic epilepsy (PMID: 29358611). ClinVar contains an entry for this variant (Variation ID: 433142). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2019 | - - |
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 25, 2017 | 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D;D;.;D;D;.;D;.;D;D
M_CAP
Benign
T
MetaRNN
Benign
T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
T
MutationTaster
Benign
D;D;D;D;D;D;D;D;D
PrimateAI
Uncertain
T
Polyphen
0.14, 0.039
.;.;B;.;B;.;.;.;B;.;B;.;.
Vest4
0.49, 0.51, 0.47, 0.48, 0.46
MVP
0.082
MPC
0.46
ClinPred
T
GERP RS
Varity_R
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at