rs1008310202
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2
The NM_001242896.3(DEPDC5):c.376G>A(p.Ala126Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,460,606 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000048 ( 0 hom. )
Consequence
DEPDC5
NM_001242896.3 missense
NM_001242896.3 missense
Scores
3
7
9
Clinical Significance
Conservation
PhyloP100: 8.60
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 3 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.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
DEPDC5 | NM_001242896.3 | c.376G>A | p.Ala126Thr | missense_variant | 7/43 | ENST00000651528.2 | NP_001229825.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DEPDC5 | ENST00000651528.2 | c.376G>A | p.Ala126Thr | missense_variant | 7/43 | NM_001242896.3 | ENSP00000498382 | P4 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD3 exomes AF: 0.00000402 AC: 1AN: 249026Hom.: 0 AF XY: 0.00000740 AC XY: 1AN XY: 135092
GnomAD3 exomes
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GnomAD4 exome AF: 0.00000479 AC: 7AN: 1460606Hom.: 0 Cov.: 33 AF XY: 0.00000688 AC XY: 5AN XY: 726624
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33
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726624
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GnomAD4 genome Cov.: 32
GnomAD4 genome
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32
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Familial focal epilepsy with variable foci Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 15, 2023 | 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. This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 126 of the DEPDC5 protein (p.Ala126Thr). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with DEPDC5-related conditions. ClinVar contains an entry for this variant (Variation ID: 466486). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Pathogenic
DEOGEN2
Benign
.;.;.;.;.;.;.;.;.;T;.;.;.;.;.;.;.;.;T;.;.;.;.;.;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D;D;D;D;D;D;D;D;.;D;.;D;D;.;.;.;D;D;.;D;D;D;D
M_CAP
Benign
D
MetaRNN
Uncertain
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
N;.;.;N;N;.;.;.;N;N;.;N;.;.;N;.;N;.;N;.;.;N;N;.;.;.
MutationTaster
Benign
D;D;D;D;D;D;D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Benign
N;.;.;.;.;.;.;.;.;N;.;N;.;.;.;.;N;.;N;.;.;N;N;.;.;.
REVEL
Benign
Sift
Uncertain
D;.;.;.;.;.;.;.;.;D;.;D;.;.;.;.;T;.;D;.;.;D;D;.;.;.
Sift4G
Uncertain
D;.;.;.;.;.;.;.;.;D;.;D;.;.;.;.;T;.;D;.;.;D;T;.;.;.
Polyphen
0.059, 0.32
.;.;.;.;.;.;.;.;B;B;.;.;.;.;.;.;B;.;B;.;.;.;.;.;.;.
Vest4
MutPred
Gain of methylation at K131 (P = 0.0626);Gain of methylation at K131 (P = 0.0626);Gain of methylation at K131 (P = 0.0626);Gain of methylation at K131 (P = 0.0626);Gain of methylation at K131 (P = 0.0626);Gain of methylation at K131 (P = 0.0626);Gain of methylation at K131 (P = 0.0626);.;Gain of methylation at K131 (P = 0.0626);Gain of methylation at K131 (P = 0.0626);.;Gain of methylation at K131 (P = 0.0626);.;Gain of methylation at K131 (P = 0.0626);Gain of methylation at K131 (P = 0.0626);.;Gain of methylation at K131 (P = 0.0626);Gain of methylation at K131 (P = 0.0626);Gain of methylation at K131 (P = 0.0626);Gain of methylation at K131 (P = 0.0626);Gain of methylation at K131 (P = 0.0626);Gain of methylation at K131 (P = 0.0626);Gain of methylation at K131 (P = 0.0626);Gain of methylation at K131 (P = 0.0626);.;.;
MVP
MPC
0.76
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
Splicing
Name
Calibrated prediction
Score
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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