rs199783404
Positions:
Variant summary
Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2
The NM_001242896.3(DEPDC5):c.2075C>T(p.Ser692Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000411 in 1,614,088 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.0021 ( 2 hom., cov: 32)
Exomes 𝑓: 0.00023 ( 0 hom. )
Consequence
DEPDC5
NM_001242896.3 missense
NM_001242896.3 missense
Scores
5
7
Clinical Significance
Conservation
PhyloP100: 2.81
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 Benign. Variant got -19 ACMG points.
PP2
?
Missense variant where missense usually causes diseases, DEPDC5
BP4
?
Computational evidence support a benign effect (MetaRNN=0.0069453716).
BP6
?
Variant 22-31822761-C-T is Benign according to our data. Variant chr22-31822761-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 414447.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31822761-C-T is described in Lovd as [Likely_benign].
BS1
?
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00211 (322/152276) while in subpopulation AFR AF= 0.00717 (298/41560). AF 95% confidence interval is 0.0065. There are 2 homozygotes in gnomad4. There are 143 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
High Homozygotes in GnomAd4 at 2 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DEPDC5 | NM_001242896.3 | c.2075C>T | p.Ser692Phe | missense_variant | 24/43 | ENST00000651528.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DEPDC5 | ENST00000651528.2 | c.2075C>T | p.Ser692Phe | missense_variant | 24/43 | NM_001242896.3 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.00210 AC: 320AN: 152158Hom.: 2 Cov.: 32
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GnomAD3 exomes AF: 0.000666 AC: 166AN: 249230Hom.: 0 AF XY: 0.000407 AC XY: 55AN XY: 135232
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GnomAD4 exome AF: 0.000233 AC: 341AN: 1461812Hom.: 0 Cov.: 30 AF XY: 0.000194 AC XY: 141AN XY: 727206
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GnomAD4 genome ? AF: 0.00211 AC: 322AN: 152276Hom.: 2 Cov.: 32 AF XY: 0.00192 AC XY: 143AN XY: 74452
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:2
Benign, criteria provided, single submitter | clinical testing | GeneDx | Jan 29, 2019 | - - |
Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jun 01, 2022 | DEPDC5: BS1, BS2 - |
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 01, 2021 | 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
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 30, 2024 | - - |
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
Uncertain
D
LIST_S2
Uncertain
D;D;D;D;D;.;D;D;.;D;.;D;D
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
Benign
T
Polyphen
0.87, 0.41
.;.;P;.;B;.;.;.;B;.;P;.;.
Vest4
0.26, 0.29, 0.27, 0.26, 0.25
MVP
0.12
MPC
0.73
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