rs312262698

Variant names:

• chr17-56844023-A-AT
• rs312262698
• NM_003647.3:c.472dupT

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_003647.3(DGKE):​c.472dupT​(p.Trp158LeufsTer8) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic,low penetrance (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DGKE NM_003647.3 frameshift
• Clinical Significance: Pathogenic, low penetrance criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.30
• Publications: 1 publications found

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]

LOC124904036 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-56844023-A-AT is Pathogenic according to our data. Variant chr17-56844023-A-AT is described in ClinVar as Pathogenic,_low_penetrance. ClinVar VariationId is 135638.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003647.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DGKE	NM_003647.3	MANE Select	c.472dupT	p.Trp158LeufsTer8	frameshift	Exon 3 of 12	NP_003638.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DGKE	ENST00000284061.8	TSL:1 MANE Select	c.472dupT	p.Trp158LeufsTer8	frameshift	Exon 3 of 12	ENSP00000284061.3
	DGKE	ENST00000572944.1	TSL:1	c.301dupT	p.Trp101fs	frameshift	Exon 2 of 10	ENSP00000458493.1
	DGKE	ENST00000576869.5	TSL:1	n.620dupT		non_coding_transcript_exon	Exon 3 of 6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic, low penetrance

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Atypical hemolytic-uremic syndrome Pathogenic:2

Sep 26, 2025

Genomenon, Inc, Genomenon, Inc

Significance: Pathogenic, low penetrance

Review Status: criteria provided, single submitter

Collection Method: curation

DGKE p.Trp158LeufsTer8 (c.472dup) is a frameshift variant that results in the production of a truncated protein which is predicted to undergo nonsense-mediated mRNA decay. This variant has been observed in at least one proband affected with atypical hemolytic-uremic syndrome (PMID:23542698). A de novo occurrence of this variant has been observed in at least one affected individual (PMID:23542698). It is absent or not present at a significant frequency in gnomAD. In conclusion, we classify DGKE p.Trp158LeufsTer8 (c.472dup) as a pathogenic, low penetrance variant.

Richard Lifton Laboratory, Yale University School of Medicine

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.3
Mutation Taster		=1/199	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs312262698; hg19: chr17-54921384;