22-31760670-A-C
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Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 4P and 5B. PM2PP2PP3BP4_StrongBP6
The NM_001242896.3(DEPDC5):āc.161A>Cā(p.Gln54Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000204 in 1,613,114 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 0.00018 ( 0 hom., cov: 31)
Exomes š: 0.00021 ( 0 hom. )
Consequence
DEPDC5
NM_001242896.3 missense
NM_001242896.3 missense
Scores
6
9
4
Clinical Significance
Conservation
PhyloP100: 8.07
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 Likely_benign. 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.
PP3
Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, BayesDel_noAF, Cadd, FATHMM_MKL, phyloP100way_vertebrate, PrimateAI, PROVEAN [when max_spliceai, MetaRNN, MutationTaster was below the threshold]
BP4
Computational evidence support a benign effect (MetaRNN=0.022509992).
BP6
Variant 22-31760670-A-C is Benign according to our data. Variant chr22-31760670-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 264749.We mark this variant Likely_benign, oryginal submissions are: {Benign=4, not_provided=1, Uncertain_significance=1, Likely_benign=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DEPDC5 | NM_001242896.3 | c.161A>C | p.Gln54Pro | missense_variant | 4/43 | ENST00000651528.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DEPDC5 | ENST00000651528.2 | c.161A>C | p.Gln54Pro | missense_variant | 4/43 | NM_001242896.3 | P4 |
Frequencies
GnomAD3 genomes AF: 0.000177 AC: 27AN: 152190Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.000366 AC: 91AN: 248584Hom.: 0 AF XY: 0.000348 AC XY: 47AN XY: 134910
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GnomAD4 exome AF: 0.000207 AC: 302AN: 1460924Hom.: 0 Cov.: 30 AF XY: 0.000249 AC XY: 181AN XY: 726776
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GnomAD4 genome AF: 0.000177 AC: 27AN: 152190Hom.: 0 Cov.: 31 AF XY: 0.000161 AC XY: 12AN XY: 74336
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:5Other:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Epilepsy, familial focal, with variable foci 1 Uncertain:1Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | New York Genome Center | Feb 19, 2021 | - - |
not provided Benign:2
Benign, criteria provided, single submitter | clinical testing | GeneDx | Jan 22, 2020 | This variant is associated with the following publications: (PMID: 26505888, 30093711) - |
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Apr 27, 2018 | - - |
Inborn genetic diseases Benign:1
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 23, 2019 | This alteration is classified as 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
Benign, criteria provided, single submitter | clinical testing | Invitae | Dec 27, 2023 | - - |
DEPDC5-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Apr 08, 2021 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
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
M_CAP
Uncertain
D
MetaRNN
Benign
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
Uncertain
M;.;.;M;M;.;.;.;M;M;.;M;.;M;.;M;.;M;.;.;M;M;.;.;.
MutationTaster
Benign
D;D;D;D;D;D;D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;.;.;.;.;.;.;.;.;D;.;D;.;.;.;D;.;D;.;.;D;D;.;.;.
REVEL
Uncertain
Sift
Pathogenic
D;.;.;.;.;.;.;.;.;D;.;D;.;.;.;D;.;D;.;.;D;D;.;.;.
Sift4G
Uncertain
D;.;.;.;.;.;.;.;.;D;.;D;.;.;.;D;.;D;.;.;D;D;.;.;.
Polyphen
1.0, 1.0
.;.;.;.;.;.;.;.;D;D;.;.;.;.;.;D;.;D;.;.;.;.;.;.;.
Vest4
MVP
MPC
1.2
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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