rs374944205
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Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate
The NM_001242896.3(DEPDC5):c.2704G>A(p.Val902Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000465 in 1,613,772 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 Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000048 ( 0 hom. )
Consequence
DEPDC5
NM_001242896.3 missense
NM_001242896.3 missense
Scores
7
12
Clinical Significance
Conservation
PhyloP100: 4.10
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 1 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), DEPDC5. . Gene score misZ 2.6501 (greater than the threshold 3.09). Trascript score misZ 3.7275 (greater than threshold 3.09). GenCC has associacion of gene with focal epilepsy, Brugada syndrome, epilepsy, familial focal, with variable foci 1, familial focal epilepsy with variable foci, autosomal dominant epilepsy with auditory features, autosomal dominant nocturnal frontal lobe epilepsy.
BP4
Computational evidence support a benign effect (MetaRNN=0.22029656).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DEPDC5 | NM_001242896.3 | c.2704G>A | p.Val902Ile | missense_variant | 29/43 | ENST00000651528.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DEPDC5 | ENST00000651528.2 | c.2704G>A | p.Val902Ile | missense_variant | 29/43 | NM_001242896.3 | P4 |
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 152046Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000160 AC: 4AN: 249574Hom.: 0 AF XY: 0.0000222 AC XY: 3AN XY: 135404
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GnomAD4 exome AF: 0.0000479 AC: 70AN: 1461726Hom.: 0 Cov.: 31 AF XY: 0.0000523 AC XY: 38AN XY: 727162
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GnomAD4 genome AF: 0.0000329 AC: 5AN: 152046Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74264
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 02, 2024 | Variant summary: DEPDC5 c.2704G>A (p.Val902Ile) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 249574 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2704G>A in individuals affected with Epilepsy, Familial Focal, With Variable Foci 1 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 466474). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 06, 2023 | The c.2704G>A (p.V902I) alteration is located in exon 29 (coding exon 28) of the DEPDC5 gene. This alteration results from a G to A substitution at nucleotide position 2704, causing the valine (V) at amino acid position 902 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Familial focal epilepsy with variable foci Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 31, 2022 | 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 466474). This variant has not been reported in the literature in individuals affected with DEPDC5-related conditions. This variant is present in population databases (rs374944205, gnomAD 0.007%). This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 902 of the DEPDC5 protein (p.Val902Ile). - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Dec 08, 2021 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
.;.;.;.;.;T;.;.;.;.;T;.;.;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;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;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
.;.;L;.;.;L;.;.;.;.;L;.;L;L;.
MutationTaster
Benign
D;D;D;D;D;D;D;N
PrimateAI
Uncertain
T
PROVEAN
Benign
N;.;.;.;.;.;N;.;.;.;N;.;.;N;.
REVEL
Benign
Sift
Benign
T;.;.;.;.;.;T;.;.;.;T;.;.;T;.
Sift4G
Uncertain
T;.;.;.;.;.;T;.;.;.;T;.;.;T;.
Polyphen
0.79
.;.;P;.;.;.;.;.;.;.;.;.;P;.;.
Vest4
MVP
MPC
0.34
ClinPred
T
GERP RS
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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