2-73938978-C-G

Variant names:

• chr2-73938978-C-G
• rs184770596
• NM_080916.3:c.211C>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PP3 BP4_Strong BS1_Supporting BS2

The NM_080916.3(DGUOK):​c.211C>G​(p.Pro71Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000355 in 1,614,010 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. P71P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00049 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00034 (4 hom.)
• Consequence: DGUOK NM_080916.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:8 B:1
• Conservation: PhyloP100: 7.42
• Publications: 4 publications found

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-AS1 (HGNC:43441): (DGUOK antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 7: BayesDel_addAF, BayesDel_noAF, Cadd, MutationAssessor, PROVEAN, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.0591152).
• BS1: Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.000341 (499/1461764) while in subpopulation AMR AF = 0.00454 (203/44722). AF 95% confidence interval is 0.00403. There are 4 homozygotes in GnomAdExome4. There are 225 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_080916.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DGUOK	NM_080916.3	MANE Select	c.211C>G	p.Pro71Ala	missense	Exon 2 of 7	NP_550438.1
	DGUOK	NM_080918.3		c.211C>G	p.Pro71Ala	missense	Exon 2 of 5	NP_550440.1
	DGUOK	NM_001318859.2		c.211C>G	p.Pro71Ala	missense	Exon 2 of 5	NP_001305788.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DGUOK	ENST00000264093.9	TSL:1 MANE Select	c.211C>G	p.Pro71Ala	missense	Exon 2 of 7	ENSP00000264093.4
	DGUOK	ENST00000418996.5	TSL:1	n.143-7741C>G		intron	N/A	ENSP00000408209.1
	DGUOK	ENST00000893377.1		c.211C>G	p.Pro71Ala	missense	Exon 2 of 7	ENSP00000563436.1

Frequencies

GnomAD3 genomes AF: 0.000493 AC: 75 AN: 152128 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00288

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.000879 AC: 221 AN: 251464 AF XY: 0.000721

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00463

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000290

Gnomad OTH exome AF: 0.00456

GnomAD4 exome AF: 0.000341 AC: 499 AN: 1461764 Hom.: 4 Cov.: 31 AF XY: 0.000309 AC XY: 225 AN XY: 727194

African (AFR) AF: 0.000120 AC: 4 AN: 33472

American (AMR) AF: 0.00454 AC: 203 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000236 AC: 262 AN: 1111914

Other (OTH) AF: 0.000480 AC: 29 AN: 60392

GnomAD4 genome AF: 0.000486 AC: 74 AN: 152246 Hom.: 0 Cov.: 32 AF XY: 0.000497 AC XY: 37 AN XY: 74442

African (AFR) AF: 0.0000482 AC: 2 AN: 41528

American (AMR) AF: 0.00281 AC: 43 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000397 AC: 27 AN: 68022

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.000281 Hom.: 0

Bravo AF: 0.000638

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000766 AC: 93

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000356

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	3	-	not provided (3)
-	2	-	not specified (2)
-	-	1	DGUOK-related disorder (1)
-	1	-	Inborn genetic diseases (1)
-	1	-	Mitochondrial disease (1)
-	1	-	Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 4;C5191055:Mitochondrial DNA depletion syndrome 3 (hepatocerebral type);CN305369:Portal hypertension, noncirrhotic, 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.95	D
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.059	T
MetaSVM	Uncertain	0.65	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		7.4
PrimateAI	Uncertain	0.51	T
PROVEAN	Pathogenic	-7.6	D
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.97	D
Vest4		0.84
MVP		1.0
MPC		0.33
ClinPred		0.24	T
GERP RS		5.3
Varity_R		0.92
gMVP		0.71
Mutation Taster		=33/67	disease causing

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

Other links and lift over

dbSNP: rs184770596; hg19: chr2-74166105;