X-50380018-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001013742.4(DGKK):c.2717G>A(p.Arg906His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000244 in 1,210,065 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 109 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 9/12 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R906C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00025 (0 hom., 8 hem., cov: 22)
  • Exomes 𝑓: 0.00024 (0 hom. 101 hem.)
• Consequence: DGKK NM_001013742.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.08

Genes affected

DGKK (HGNC:32395): (diacylglycerol kinase kappa) The protein encoded by this gene is an enzyme that phosphorylates diacylglycerol, converting it to phosphatidic acid. The encoded protein is a membrane protein and is inhibited by hydrogen peroxide. Variations in this gene have been associated with hypospadias. [provided by RefSeq, Mar 2011]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005242914).
• BS2: High Hemizygotes in GnomAd at 8 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DGKK	NM_001013742.4	c.2717G>A	p.Arg906His	missense_variant	19/28	ENST00000611977.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DGKK	ENST00000611977.2	c.2717G>A	p.Arg906His	missense_variant	19/28	1	NM_001013742.4	P1

Frequencies

GnomAD3 genomes AF: 0.000250 AC: 28 AN: 112116 Hom.: 0 Cov.: 22 AF XY: 0.000233 AC XY: 8 AN XY: 34284

Gnomad AFR AF: 0.000227

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000661

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00225

Gnomad SAS AF: 0.00113

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000376

Gnomad OTH AF: 0.000662

GnomAD3 exomes AF: 0.000563 AC: 102 AN: 181180 Hom.: 0 AF XY: 0.000594 AC XY: 40 AN XY: 67334

Gnomad AFR exome AF: 0.000161

Gnomad AMR exome AF: 0.000694

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00207

Gnomad SAS exome AF: 0.00184

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000185

Gnomad OTH exome AF: 0.000674

GnomAD4 exome AF: 0.000243 AC: 267 AN: 1097892 Hom.: 0 Cov.: 30 AF XY: 0.000278 AC XY: 101 AN XY: 363362

Gnomad4 AFR exome AF: 0.0000379

Gnomad4 AMR exome AF: 0.000682

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00139

Gnomad4 SAS exome AF: 0.00185

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000891

Gnomad4 OTH exome AF: 0.000521

GnomAD4 genome AF: 0.000250 AC: 28 AN: 112173 Hom.: 0 Cov.: 22 AF XY: 0.000233 AC XY: 8 AN XY: 34351

Gnomad4 AFR AF: 0.000226

Gnomad4 AMR AF: 0.000660

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00225

Gnomad4 SAS AF: 0.00114

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000376

Gnomad4 OTH AF: 0.000654

Alfa AF: 0.000285 Hom.: 2

Bravo AF: 0.000457

ExAC AF: 0.000637 AC: 77

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 23, 2023

The c.2717G>A (p.R906H) alteration is located in exon 19 (coding exon 19) of the DGKK gene. This alteration results from a G to A substitution at nucleotide position 2717, causing the arginine (R) at amino acid position 906 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.64
Cadd	Benign	17
Dann	Benign	0.84
DEOGEN2	Benign	0.050	T
FATHMM_MKL	Benign	0.59	D
LIST_S2	Uncertain	0.94	D
MetaRNN	Benign	0.0052	T
PrimateAI	Benign	0.36	T
Sift4G	Pathogenic	0.0010	D
Polyphen		0.13	B
Vest4		0.062
MVP		0.21
GERP RS		2.5
Varity_R		0.085
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs782600344; hg19: chrX-50123016; COSMIC: COSV65706848;