chr2-73926914-G-T

Position:

chr2-73926914-G-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_080916.3(DGUOK):c.4G>T(p.Ala2Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00482 in 1,613,382 control chromosomes in the GnomAD database, including 28 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). Synonymous variant affecting the same amino acid position (i.e. A2A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0030 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0050 ( 27 hom. )

Consequence

DGUOK
NM_080916.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:6O:1

Conservation

PhyloP100: -0.201

Variant links:

Genes affected

DGUOK (HGNC:2858): (deoxyguanosine kinase) In mammalian cells, the phosphorylation of purine deoxyribonucleosides is mediated predominantly by two deoxyribonucleoside kinases, cytosolic deoxycytidine kinase and mitochondrial deoxyguanosine kinase. The protein encoded by this gene is responsible for phosphorylation of purine deoxyribonucleosides in the mitochondrial matrix. In addition, this protein phosphorylates several purine deoxyribonucleoside analogs used in the treatment of lymphoproliferative disorders, and this phosphorylation is critical for the effectiveness of the analogs. Alternative splice variants encoding different protein isoforms have been described for this gene. [provided by RefSeq, Jul 2008]

DGUOK links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0109478235).

BP6

Variant 2-73926914-G-T is Benign according to our data. Variant chr2-73926914-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 193482.We mark this variant Likely_benign, oryginal submissions are: {not_provided=1, Likely_benign=2, Uncertain_significance=3, Benign=2}.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00296 (451/152350) while in subpopulation NFE AF= 0.00512 (348/68010). AF 95% confidence interval is 0.00467. There are 1 homozygotes in gnomad4. There are 179 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 27 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DGUOK	NM_080916.3 linkuse as main transcript	c.4G>T	p.Ala2Ser	missense_variant	1/7	ENST00000264093.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DGUOK	ENST00000264093.9 linkuse as main transcript	c.4G>T	p.Ala2Ser	missense_variant	1/7	1	NM_080916.3	P1	Q16854-1

Frequencies

GnomAD3 genomes

AF:

0.00297

AC:

452

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000989

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.00268

Gnomad ASJ

AF:

0.000864

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00513

Gnomad OTH

AF:

0.00717

GnomAD3 exomes

AF:

0.00255

AC:

639

AN:

250362

Hom.:

AF XY:

0.00247

AC XY:

335

AN XY:

135558

show subpopulations

Gnomad AFR exome

AF:

0.000865

Gnomad AMR exome

AF:

0.00260

Gnomad ASJ exome

AF:

0.00109

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000457

Gnomad FIN exome

AF:

0.000143

Gnomad NFE exome

AF:

0.00435

Gnomad OTH exome

AF:

0.00212

GnomAD4 exome

AF:

0.00501

AC:

7327

AN:

1461032

Hom.:

Cov.:

AF XY:

0.00482

AC XY:

3501

AN XY:

726856

show subpopulations

Gnomad4 AFR exome

AF:

0.00105

Gnomad4 AMR exome

AF:

0.00248

Gnomad4 ASJ exome

AF:

0.000727

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000545

Gnomad4 FIN exome

AF:

0.0000951

Gnomad4 NFE exome

AF:

0.00612

Gnomad4 OTH exome

AF:

0.00502

GnomAD4 genome

AF:

0.00296

AC:

451

AN:

152350

Hom.:

Cov.:

AF XY:

0.00240

AC XY:

179

AN XY:

74502

show subpopulations

Gnomad4 AFR

AF:

0.000986

Gnomad4 AMR

AF:

0.00268

Gnomad4 ASJ

AF:

0.000864

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.00512

Gnomad4 OTH

AF:

0.00710

Alfa

AF:

0.00412

Hom.:

Bravo

AF:

0.00325

TwinsUK

AF:

0.00485

AC:

ALSPAC

AF:

0.00778

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00442

AC:

ExAC

AF:

0.00234

AC:

284

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00518

EpiControl

AF:

0.00462

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7Benign:6Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:6Benign:4

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 20, 2020	This variant is associated with the following publications: (PMID: 19748572, 18828154, 22622127, 17073823) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	DGUOK: BS2 -
Uncertain significance, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 08, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 03, 2018	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 18, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The DGUOK p.Ala2Ser variant was identified as a compound heterozygous variant in two pediatric cases with mitochondrial DNA depletion syndrome (Mousson_de_Camaret_2007_PMID: 17073823; Buchaklian_2012_PMID: 22622127). The variant was identified in dbSNP (ID: rs147551003) and ClinVar (classified as uncertain significance by Children's Mercy Hospital, GeneDx, Mayo Clinic, EGL Genetic Diagnostics, CeGaT Praxis; and as benign by Invitae and Mendelics). The variant was identified in control databases in 727 of 281762 chromosomes (3 homozygous) at a frequency of 0.00258 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 570 of 128878 chromosomes (freq: 0.004423), Latino in 91 of 35430 chromosomes (freq: 0.002568), Other in 16 of 7212 chromosomes (freq: 0.002219), Ashkenazi Jewish in 11 of 10352 chromosomes (freq: 0.001063), African in 22 of 24908 chromosomes (freq: 0.000883), South Asian in 14 of 30616 chromosomes (freq: 0.000457) and European (Finnish) in 3 of 24434 chromosomes (freq: 0.000123), but was not observed in the East Asian population. The p.Ala2 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -
Uncertain significance, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Mitochondrial DNA depletion syndrome 3 (hepatocerebral type)

Uncertain:1Benign:1Other:1

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpretted as Uncertain significance and reported on 10/30/2014 by GTR ID 320384. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

DGUOK-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 12, 2021

This variant is classified as likely 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

0.11

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.15

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.26

.;T;.

Eigen

Benign

-0.75

Eigen_PC

Benign

-0.76

FATHMM_MKL

Benign

0.50

LIST_S2

Benign

0.52

T;T;T

M_CAP

Uncertain

0.21

MetaRNN

Benign

0.011

T;T;T

MetaSVM

Uncertain

0.52

MutationAssessor

Uncertain

2.0

M;M;M

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.12

.;N;N

REVEL

Benign

0.23

Sift

Benign

0.053

.;T;D

Sift4G

Benign

0.14

T;T;T

Polyphen

0.043

.;B;.

Vest4

0.74

MVP

0.90

MPC

0.15

ClinPred

0.0097

GERP RS

1.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.1

Varity_R

0.058

gMVP

0.55

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over