17-56834830-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

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. 13/21 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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 1.07

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]

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

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• 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 id is 290120.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=3, Benign=2}. Variant chr17-56834830-C-T is described in Lovd as [Likely_benign]. Variant chr17-56834830-C-T is described in Lovd as [Benign].
• 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DGKE	NM_003647.3	c.35C>T	p.Pro12Leu	missense_variant	2/12	ENST00000284061.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DGKE	ENST00000284061.8	c.35C>T	p.Pro12Leu	missense_variant	2/12	1	NM_003647.3	P1
DGKE	ENST00000572810.1	c.35C>T	p.Pro12Leu	missense_variant	2/2	1
DGKE	ENST00000576869.5	n.183C>T		non_coding_transcript_exon_variant	2/6	1
C17orf67	ENST00000487705.1	n.285+3659G>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.00466 AC: 709 AN: 152210 Hom.: 2 Cov.: 33

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

GnomAD3 exomes AF: 0.00466 AC: 1141 AN: 244598 Hom.: 5 AF XY: 0.00480 AC XY: 639 AN XY: 133244

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 SAS exome AF: 0.00214

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.: 33 Cov.: 31 AF XY: 0.00695 AC XY: 5029 AN XY: 724050

Gnomad4 AFR exome AF: 0.00108

Gnomad4 AMR exome AF: 0.00357

Gnomad4 ASJ exome AF: 0.00512

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00247

Gnomad4 FIN exome AF: 0.00114

Gnomad4 NFE exome AF: 0.00841

Gnomad4 OTH exome AF: 0.00569

GnomAD4 genome AF: 0.00465 AC: 709 AN: 152328 Hom.: 2 Cov.: 33 AF XY: 0.00408 AC XY: 304 AN XY: 74474

Gnomad4 AFR AF: 0.00120

Gnomad4 AMR AF: 0.00366

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00186

Gnomad4 FIN AF: 0.000847

Gnomad4 NFE AF: 0.00817

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00709 Hom.: 9

Bravo AF: 0.00494

TwinsUK AF: 0.00485 AC: 18

ALSPAC AF: 0.00778 AC: 30

ESP6500AA AF: 0.000684 AC: 3

ESP6500EA AF: 0.00806 AC: 69

ExAC AF: 0.00467 AC: 566

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00769

EpiControl AF: 0.00699

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 02, 2016	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 25, 2021	- -

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2023	DGKE: BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 15, 2024	- -

Kidney disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 12, 2016

- -

DGKE-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 19, 2022

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	20
Dann	Uncertain	1.0
DEOGEN2	Benign	0.072	T;.
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.049	N
LIST_S2	Benign	0.63	T;T
M_CAP	Benign	0.0085	T
MetaRNN	Benign	0.0040	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.76	N;.
REVEL	Benign	0.042
Sift	Uncertain	0.018	D;.
Sift4G	Uncertain	0.047	D;D
Polyphen		0.089	B;.
Vest4		0.31
MVP		0.59
MPC		0.41
ClinPred		0.017	T
GERP RS		3.6
Varity_R		0.033
gMVP		0.50

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

LitVar

Other links and lift over

dbSNP: rs146866423; hg19: chr17-54912191; COSMIC: COSV99033591; COSMIC: COSV99033591;