X-50382602-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001013742.4(DGKK):c.2551C>T(p.Arg851Cys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00337 in 1,190,741 control chromosomes in the GnomAD database, including 95 homozygotes. There are 1,065 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. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.018 (48 hom., 542 hem., cov: 24)
  • Exomes 𝑓: 0.0019 (47 hom. 523 hem.)
• Consequence: DGKK NM_001013742.4 missense, splice_region
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.18

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016780794).
• BP6: Variant X-50382602-G-A is Benign according to our data. Variant chrX-50382602-G-A is described in ClinVar as [Benign]. Clinvar id is 785699.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0598 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DGKK	NM_001013742.4	c.2551C>T	p.Arg851Cys	missense_variant, splice_region_variant	18/28	ENST00000611977.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DGKK	ENST00000611977.2	c.2551C>T	p.Arg851Cys	missense_variant, splice_region_variant	18/28	1	NM_001013742.4	P1

Frequencies

GnomAD3 genomes AF: 0.0179 AC: 1998 AN: 111789 Hom.: 48 Cov.: 24 AF XY: 0.0160 AC XY: 545 AN XY: 33985

Gnomad AFR AF: 0.0623

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00598

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000376

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000150

Gnomad OTH AF: 0.00996

GnomAD3 exomes AF: 0.00485 AC: 837 AN: 172620 Hom.: 21 AF XY: 0.00351 AC XY: 209 AN XY: 59486

Gnomad AFR exome AF: 0.0603

Gnomad AMR exome AF: 0.00323

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000606

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000153

Gnomad OTH exome AF: 0.00190

GnomAD4 exome AF: 0.00187 AC: 2018 AN: 1078899 Hom.: 47 Cov.: 26 AF XY: 0.00151 AC XY: 523 AN XY: 345551

Gnomad4 AFR exome AF: 0.0632

Gnomad4 AMR exome AF: 0.00319

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000135

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000483

Gnomad4 OTH exome AF: 0.00454

GnomAD4 genome AF: 0.0178 AC: 1995 AN: 111842 Hom.: 48 Cov.: 24 AF XY: 0.0159 AC XY: 542 AN XY: 34048

Gnomad4 AFR AF: 0.0621

Gnomad4 AMR AF: 0.00588

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000377

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000150

Gnomad4 OTH AF: 0.00984

Alfa AF: 0.00231 Hom.: 88

Bravo AF: 0.0210

ESP6500AA AF: 0.0571 AC: 180

ESP6500EA AF: 0.000156 AC: 1

ExAC AF: 0.00518 AC: 626

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.72
Cadd	Benign	12
Dann	Benign	0.70
DEOGEN2	Benign	0.014	T
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.72	T
MetaRNN	Benign	0.0017	T
PrimateAI	Benign	0.29	T
Sift4G	Benign	0.13	T
Polyphen		0.036	B
Vest4		0.048
MVP		0.18
GERP RS		1.1
Varity_R		0.15
gMVP		0.58

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: rs144819611; hg19: chrX-50125600;