chr17-56834912-G-C
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Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_003647.3(DGKE):āc.117G>Cā(p.Trp39Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,613,720 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Genomes: š 0.000046 ( 0 hom., cov: 33)
Exomes š: 0.000011 ( 0 hom. )
Consequence
DGKE
NM_003647.3 missense
NM_003647.3 missense
Scores
1
15
3
Clinical Significance
Conservation
PhyloP100: 9.15
Genes affected
DGKE (HGNC:2852): (diacylglycerol kinase epsilon) Diacylglycerol kinases are thought to be involved mainly in the regeneration of phosphatidylinositol (PI) from diacylglycerol in the PI-cycle during cell signal transduction. When expressed in mammalian cells, DGK-epsilon shows specificity for arachidonyl-containing diacylglycerol. DGK-epsilon is expressed predominantly in testis. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
DGKE | NM_003647.3 | c.117G>C | p.Trp39Cys | missense_variant | 2/12 | ENST00000284061.8 | NP_003638.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DGKE | ENST00000284061.8 | c.117G>C | p.Trp39Cys | missense_variant | 2/12 | 1 | NM_003647.3 | ENSP00000284061 | P1 | |
DGKE | ENST00000572810.1 | c.117G>C | p.Trp39Cys | missense_variant | 2/2 | 1 | ENSP00000459295 | |||
DGKE | ENST00000576869.5 | n.265G>C | non_coding_transcript_exon_variant | 2/6 | 1 | |||||
C17orf67 | ENST00000487705.1 | n.285+3577C>G | intron_variant, non_coding_transcript_variant | 2 |
Frequencies
GnomAD3 genomes AF: 0.0000460 AC: 7AN: 152230Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000120 AC: 3AN: 250118Hom.: 0 AF XY: 0.00000739 AC XY: 1AN XY: 135378
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GnomAD4 exome AF: 0.0000109 AC: 16AN: 1461372Hom.: 0 Cov.: 31 AF XY: 0.0000151 AC XY: 11AN XY: 727032
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GnomAD4 genome AF: 0.0000459 AC: 7AN: 152348Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3AN XY: 74494
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Dec 13, 2019 | DNA sequence analysis of the DGKE gene demonstrated a sequence change, c.117G>C, in exon 2 that results in an amino acid change, p.Trp39Cys. This sequence change does not appear to have been previously described in patients with DGKE-related disorders and has been described in the gnomAD database in three individuals (dbSNP rs201377251). The p.Trp39Cys change affects a highly conserved amino acid residue located in a domain of the DGKE protein that is not known to be functional. The p.Trp39Cys substitution appears to be mostly deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). - |
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 20, 2023 | Variant summary: DGKE c.117G>C (p.Trp39Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 250118 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.117G>C in individuals affected with Nephrotic Syndrome, Type 7 and no experimental evidence demonstrating its impact on protein function have been reported. One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
T;.
Eigen
Uncertain
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D
M_CAP
Benign
D
MetaRNN
Uncertain
D;D
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;M
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;.
REVEL
Uncertain
Sift
Uncertain
D;.
Sift4G
Uncertain
D;D
Polyphen
D;.
Vest4
MutPred
Loss of MoRF binding (P = 0.033);Loss of MoRF binding (P = 0.033);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
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