X-50376824-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001013742.4(DGKK):c.3206G>A(p.Ser1069Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00659 in 1,206,913 control chromosomes in the GnomAD database, including 31 homozygotes. There are 2,527 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 9/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0060 (2 hom., 190 hem., cov: 23)
  • Exomes 𝑓: 0.0066 (29 hom. 2337 hem.)
• Consequence: DGKK NM_001013742.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.228

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=0.005743742).
• BP6: Variant X-50376824-C-T is Benign according to our data. Variant chrX-50376824-C-T is described in ClinVar as [Benign]. Clinvar id is 719275.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00665 (7274/1094495) while in subpopulation MID AF= 0.0216 (87/4036). AF 95% confidence interval is 0.0179. There are 29 homozygotes in gnomad4_exome. There are 2337 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DGKK	NM_001013742.4	c.3206G>A	p.Ser1069Asn	missense_variant	23/28	ENST00000611977.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DGKK	ENST00000611977.2	c.3206G>A	p.Ser1069Asn	missense_variant	23/28	1	NM_001013742.4	P1

Frequencies

GnomAD3 genomes AF: 0.00602 AC: 676 AN: 112366 Hom.: 2 Cov.: 23 AF XY: 0.00551 AC XY: 190 AN XY: 34514

Gnomad AFR AF: 0.000842

Gnomad AMI AF: 0.00585

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.0286

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000749

Gnomad FIN AF: 0.0107

Gnomad MID AF: 0.0252

Gnomad NFE AF: 0.00871

Gnomad OTH AF: 0.00596

GnomAD3 exomes AF: 0.00654 AC: 1154 AN: 176497 Hom.: 7 AF XY: 0.00595 AC XY: 375 AN XY: 63017

Gnomad AFR exome AF: 0.000817

Gnomad AMR exome AF: 0.00128

Gnomad ASJ exome AF: 0.0282

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000778

Gnomad FIN exome AF: 0.00892

Gnomad NFE exome AF: 0.00905

Gnomad OTH exome AF: 0.00789

GnomAD4 exome AF: 0.00665 AC: 7274 AN: 1094495 Hom.: 29 Cov.: 30 AF XY: 0.00649 AC XY: 2337 AN XY: 360285

Gnomad4 AFR exome AF: 0.00114

Gnomad4 AMR exome AF: 0.00146

Gnomad4 ASJ exome AF: 0.0277

Gnomad4 EAS exome AF: 0.0000332

Gnomad4 SAS exome AF: 0.00117

Gnomad4 FIN exome AF: 0.00974

Gnomad4 NFE exome AF: 0.00689

Gnomad4 OTH exome AF: 0.00714

GnomAD4 genome AF: 0.00600 AC: 674 AN: 112418 Hom.: 2 Cov.: 23 AF XY: 0.00550 AC XY: 190 AN XY: 34576

Gnomad4 AFR AF: 0.000840

Gnomad4 AMR AF: 0.00216

Gnomad4 ASJ AF: 0.0286

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000752

Gnomad4 FIN AF: 0.0107

Gnomad4 NFE AF: 0.00871

Gnomad4 OTH AF: 0.00588

Alfa AF: 0.00955 Hom.: 415

Bravo AF: 0.00519

TwinsUK AF: 0.00809 AC: 30

ALSPAC AF: 0.00554 AC: 16

ESP6500AA AF: 0.000884 AC: 3

ESP6500EA AF: 0.0110 AC: 71

ExAC AF: 0.00727 AC: 879

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	0.081
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.85
Cadd	Benign	5.2
Dann	Benign	0.69
DEOGEN2	Benign	0.017	T
FATHMM_MKL	Benign	0.041	N
LIST_S2	Benign	0.16	T
MetaRNN	Benign	0.0057	T
MutationAssessor	Uncertain	2.3	M
PrimateAI	Benign	0.31	T
Sift4G	Benign	0.31	T
Polyphen		0.17	B
Vest4		0.036
MVP		0.16
GERP RS		1.1
Varity_R		0.061
gMVP		0.43

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs139988151; hg19: chrX-50119823;