chr17-56834830-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2

The NM_003647.3(DGKE):c.35C>T(p.Pro12Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00683 in 1,608,714 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0047 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0071 ( 33 hom. )

Consequence

DGKE
NM_003647.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:8

Conservation

PhyloP100: 1.07

Publications

7 publications found

Variant links:

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]

DGKE links:

C17orf67 (HGNC:27900): (chromosome 17 open reading frame 67) Predicted to be located in extracellular region. [provided by Alliance of Genome Resources, Apr 2022]

C17orf67 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 4 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 0.59049 (below the threshold of 3.09). Trascript score misZ: 0.87515 (below the threshold of 3.09). GenCC associations: The gene is linked to immunoglobulin-mediated membranoproliferative glomerulonephritis, atypical hemolytic-uremic syndrome with DGKE deficiency.

BP4

Computational evidence support a benign effect (MetaRNN=0.0040314496).

BP6

Variant 17-56834830-C-T is Benign according to our data. Variant chr17-56834830-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 290120.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00465 (709/152328) while in subpopulation NFE AF = 0.00817 (556/68034). AF 95% confidence interval is 0.00761. There are 2 homozygotes in GnomAd4. There are 304 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DGKE	NM_003647.3	MANE Select	c.35C>T	p.Pro12Leu	missense	Exon 2 of 12	NP_003638.1	A1L4Q0

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DGKE	ENST00000284061.8	TSL:1 MANE Select	c.35C>T	p.Pro12Leu	missense	Exon 2 of 12	ENSP00000284061.3	P52429-1
DGKE	ENST00000572810.1	TSL:1	c.35C>T	p.Pro12Leu	missense	Exon 2 of 2	ENSP00000459295.1	P52429-2
DGKE	ENST00000576869.5	TSL:1	n.183C>T		non_coding_transcript_exon	Exon 2 of 6

Frequencies

GnomAD3 genomes

AF:

0.00466

AC:

709

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00121

Gnomad AMI

AF:

0.0110

Gnomad AMR

AF:

0.00366

Gnomad ASJ

AF:

0.00346

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00186

Gnomad FIN

AF:

0.000847

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00817

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.00466

AC:

1141

AN:

244598

AF XY:

0.00480

show subpopulations

Gnomad AFR exome

AF:

0.00138

Gnomad AMR exome

AF:

0.00337

Gnomad ASJ exome

AF:

0.00557

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000724

Gnomad NFE exome

AF:

0.00768

Gnomad OTH exome

AF:

0.00401

GnomAD4 exome

AF:

0.00706

AC:

10281

AN:

1456386

Hom.:

Cov.:

AF XY:

0.00695

AC XY:

5029

AN XY:

724050

show subpopulations

African (AFR)

AF:

0.00108

AC:

AN:

33390

American (AMR)

AF:

0.00357

AC:

159

AN:

44562

Ashkenazi Jewish (ASJ)

AF:

0.00512

AC:

133

AN:

25984

East Asian (EAS)

AF:

0.00

AC:

AN:

39624

South Asian (SAS)

AF:

0.00247

AC:

212

AN:

85980

European-Finnish (FIN)

AF:

0.00114

AC:

AN:

51972

Middle Eastern (MID)

AF:

0.00126

AC:

AN:

4770

European-Non Finnish (NFE)

AF:

0.00841

AC:

9334

AN:

1110000

Other (OTH)

AF:

0.00569

AC:

342

AN:

60104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

650

1299

1949

2598

3248

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

354

708

1062

1416

1770

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00465

AC:

709

AN:

152328

Hom.:

Cov.:

AF XY:

0.00408

AC XY:

304

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.00120

AC:

AN:

41572

American (AMR)

AF:

0.00366

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00346

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5164

South Asian (SAS)

AF:

0.00186

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.000847

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00817

AC:

556

AN:

68034

Other (OTH)

AF:

0.00284

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

101

135

169

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00677

Hom.:

Bravo

AF:

0.00494

TwinsUK

AF:

0.00485

AC:

ALSPAC

AF:

0.00778

AC:

ESP6500AA

AF:

0.000684

AC:

ESP6500EA

AF:

0.00806

AC:

ExAC

AF:

0.00467

AC:

566

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00769

EpiControl

AF:

0.00699

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (3)

DGKE-related disorder (1)

Kidney disorder (1)

Mesangiocapillary glomerulonephritis;C3554330:Immunoglobulin-mediated membranoproliferative glomerulonephritis (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.48

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.072

Eigen

Benign

-0.46

Eigen_PC

Benign

-0.37

FATHMM_MKL

Benign

0.049

LIST_S2

Benign

0.63

M_CAP

Benign

0.0085

MetaRNN

Benign

0.0040

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.7

PhyloP100

1.1

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-0.76

REVEL

Benign

0.042

Sift

Uncertain

0.018

Sift4G

Uncertain

0.047

Polyphen

0.089

Vest4

0.31

MVP

0.59

MPC

0.41

ClinPred

0.017

GERP RS

3.6

PromoterAI

0.036

Neutral

(source)

Varity_R

0.033

gMVP

0.50

Mutation Taster

=96/4

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over