22-31797674-A-T
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP6
The NM_001242896.3(DEPDC5):c.842A>T(p.Tyr281Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000384 in 1,613,886 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001242896.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DEPDC5 | ENST00000651528.2 | c.842A>T | p.Tyr281Phe | missense_variant | Exon 13 of 43 | NM_001242896.3 | ENSP00000498382.1 | |||
ENSG00000285404 | ENST00000646701.1 | c.758A>T | p.Tyr253Phe | missense_variant | Exon 11 of 21 | ENSP00000496158.1 |
Frequencies
GnomAD3 genomes AF: 0.0000592 AC: 9AN: 152124Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000281 AC: 7AN: 249160Hom.: 0 AF XY: 0.0000370 AC XY: 5AN XY: 135152
GnomAD4 exome AF: 0.0000363 AC: 53AN: 1461762Hom.: 0 Cov.: 30 AF XY: 0.0000426 AC XY: 31AN XY: 727186
GnomAD4 genome AF: 0.0000592 AC: 9AN: 152124Hom.: 0 Cov.: 31 AF XY: 0.0000808 AC XY: 6AN XY: 74288
ClinVar
Submissions by phenotype
not provided Benign:2
This variant is associated with the following publications: (PMID: 27683934, 29359340, 30080265, 27066554, 30093711, 31639411) -
DEPDC5: BS3:Supporting -
Inborn genetic diseases Uncertain:1
The p.Y281F variant (also known as c.842A>T), located in coding exon 12 of the DEPDC5 gene, results from an A to T substitution at nucleotide position 842. The tyrosine at codon 281 is replaced by phenylalanine, an amino acid with highly similar properties. This variant has been reported in an individual with infantile spasms and focal cortical dysplasia on MRI; in addition, this variant was inherited from a father with unspecified epilepsy and also detected in a full sibling with multifocal epilepsy (Carvill GL et al. Neurol Genet, 2015 Aug;1:e17). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be benign and deleterious by PolyPhen and SIFT in silico analyses, respectively. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Familial focal epilepsy with variable foci Uncertain:1
This sequence change replaces tyrosine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 281 of the DEPDC5 protein (p.Tyr281Phe). This variant is present in population databases (rs200797928, gnomAD 0.01%). This missense change has been observed in individuals with clinical features of DEPDC5-related conditions (PMID: 27066554; internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 264753). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. -
Epilepsy, familial focal, with variable foci 1 Other:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at