X-50384201-T-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001013742.4(DGKK):c.2516A>C(p.Asn839Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,068,919 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 8/12 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.000011 (0 hom. 5 hem.)
• Consequence: DGKK NM_001013742.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.91

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07195109).
• BS2: High Hemizygotes in GnomAdExome at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DGKK	NM_001013742.4	c.2516A>C	p.Asn839Thr	missense_variant	17/28	ENST00000611977.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DGKK	ENST00000611977.2	c.2516A>C	p.Asn839Thr	missense_variant	17/28	1	NM_001013742.4	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.0000352 AC: 5 AN: 142161 Hom.: 1 AF XY: 0.0000485 AC XY: 2 AN XY: 41217

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000138

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000498

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000112 AC: 12 AN: 1068919 Hom.: 0 Cov.: 25 AF XY: 0.0000146 AC XY: 5 AN XY: 343499

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: 0.0000395

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000848

Gnomad4 OTH exome AF: 0.0000446

GnomAD4 genome Cov.: 23

Alfa AF: 0.000111 Hom.: 0

ExAC AF: 0.0000339 AC: 4

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

Jan 24, 2023

The c.2516A>C (p.N839T) alteration is located in exon 17 (coding exon 17) of the DGKK gene. This alteration results from a A to C substitution at nucleotide position 2516, causing the asparagine (N) at amino acid position 839 to be replaced by a threonine (T). 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	0.14
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.57
Cadd	Benign	17
Dann	Benign	0.73
DEOGEN2	Benign	0.025	T
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.68	T
MetaRNN	Benign	0.072	T
PrimateAI	Uncertain	0.63	T
Sift4G	Benign	0.14	T
Polyphen		0.013	B
Vest4		0.066
MVP		0.28
GERP RS		3.7
Varity_R		0.21
gMVP		0.57

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: rs782238611; hg19: chrX-50127199;