rs578185749
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001242896.3(DEPDC5):c.2620C>T(p.Arg874Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000137 in 1,461,480 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R874R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_001242896.3 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DEPDC5 | NM_001242896.3 | c.2620C>T | p.Arg874Ter | stop_gained | 28/43 | ENST00000651528.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DEPDC5 | ENST00000651528.2 | c.2620C>T | p.Arg874Ter | stop_gained | 28/43 | NM_001242896.3 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461480Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2AN XY: 727038
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Epilepsy, familial focal, with variable foci 1 Pathogenic:1Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | Mar 01, 2023 | The stop gained variant c.2620C>T(p.Arg874Ter) in the DEPDC5 gene has been reported previously in heterozygous state in multiple individuals affected with focal epilepsies (Lal D, et al., 2014; Baldassari S, et al., 2016). This variant is novel in the gnomAD Exomes and 1000 Genomes. It is submitted to ClinVar as Pathogenic. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic. - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Familial focal epilepsy with variable foci Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 17, 2022 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 264737). This premature translational stop signal has been observed in individual(s) with epilepsy (PMID: 24591017, 30093711). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg874*) in the DEPDC5 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DEPDC5 are known to be pathogenic (PMID: 23542697, 23542701). - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 02, 2022 | Reported previously as p.(R865*) due to alternate nomenclature in three family members with seizures and/or intellectual disability (Lal et al., 2014); Reported previously in an individual with seizures; inherited from the father with somnambulism (Baldassari et al., 2019); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30093711, 29281825, 32574724, 34196989, 33949696, 33741238, 24591017) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at