17-56844085-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_003647.3(DGKE):c.531T>G(p.Cys177Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000698 in 1,431,964 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: DGKE NM_003647.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.14

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]

TRIM25 (HGNC:12932): (tripartite motif containing 25) The protein encoded by this gene is a member of the tripartite motif (TRIM) family. The TRIM motif includes three zinc-binding domains, a RING, a B-box type 1 and a B-box type 2, and a coiled-coil region. The protein is an RNA binding protein, functions as a ubiquitin E3 ligase and is involved in multiple cellular processes, including regulation of antiviral innate immunity. [provided by RefSeq, Sep 2021]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DGKE	NM_003647.3	c.531T>G	p.Cys177Trp	missense_variant	3/12	ENST00000284061.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DGKE	ENST00000284061.8	c.531T>G	p.Cys177Trp	missense_variant	3/12	1	NM_003647.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.98e-7 AC: 1 AN: 1431964 Hom.: 0 Cov.: 30 AF XY: 0.00000140 AC XY: 1 AN XY: 712206

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000124

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Immunoglobulin-mediated membranoproliferative glomerulonephritis Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

-

The missense variant in c.531T>G (p.Cys177Trp) in DGKE gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Cys177Trp variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. The amino acid Cys at position 177 is changed to a Trp changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. The amino acid change p.Cys177Trp in DGKE is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.76	D
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.87	D
M_CAP	Pathogenic	0.61	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Pathogenic	3.7	H
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-8.9	D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.90
MutPred		0.83		Loss of methylation at K176 (P = 0.0248);
MVP		0.98
MPC		1.2
ClinPred		0.99	D
GERP RS		4.5
Varity_R		0.84
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-54921446;