rs567251538

Variant names:

• chr2-73926849-C-CAGCG
• rs567251538
• ENST00000893377.1:c.-60_-57dupGCGA

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The ENST00000348222.3(DGUOK):​c.-60_-57dupGCGA variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00407 in 1,609,590 control chromosomes in the GnomAD database, including 25 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0030 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0042 (23 hom.)
• Consequence: DGUOK ENST00000348222.3 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.46
• Publications: 0 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 Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• mitochondrial DNA depletion syndrome 3 (hepatocerebral type)

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 4

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• portal hypertension, noncirrhotic

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00302 (460/152362) while in subpopulation NFE AF = 0.00453 (308/68026). AF 95% confidence interval is 0.00411. There are 2 homozygotes in GnomAd4. There are 223 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000348222.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DGUOK	NM_080916.3	MANE Select	c.-62_-61insAGCG		upstream_gene	N/A	NP_550438.1	E5KSL5
	DGUOK	NM_080918.3		c.-62_-61insAGCG		upstream_gene	N/A	NP_550440.1	Q16854-2
	DGUOK	NM_001318859.2		c.-62_-61insAGCG		upstream_gene	N/A	NP_001305788.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DGUOK	ENST00000893377.1		c.-60_-57dupGCGA		5_prime_UTR	Exon 1 of 7	ENSP00000563436.1
	DGUOK	ENST00000348222.3	TSL:2	c.-60_-57dupGCGA		5_prime_UTR	Exon 1 of 5	ENSP00000306964.3	Q16854-2
	DGUOK	ENST00000893378.1		c.-60_-57dupGCGA		5_prime_UTR	Exon 1 of 5	ENSP00000563437.1

Frequencies

GnomAD3 genomes AF: 0.00302 AC: 460 AN: 152244 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000796

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00772

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00453

Gnomad OTH AF: 0.00191

GnomAD4 exome AF: 0.00417 AC: 6083 AN: 1457228 Hom.: 23 Cov.: 32 AF XY: 0.00408 AC XY: 2959 AN XY: 725066

African (AFR) AF: 0.000568 AC: 19 AN: 33468

American (AMR) AF: 0.00152 AC: 68 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00107 AC: 28 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.000487 AC: 42 AN: 86172

European-Finnish (FIN) AF: 0.00847 AC: 418 AN: 49376

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5758

European-Non Finnish (NFE) AF: 0.00479 AC: 5322 AN: 1111600

Other (OTH) AF: 0.00307 AC: 185 AN: 60330

GnomAD4 genome AF: 0.00302 AC: 460 AN: 152362 Hom.: 2 Cov.: 33 AF XY: 0.00299 AC XY: 223 AN XY: 74506

African (AFR) AF: 0.000793 AC: 33 AN: 41590

American (AMR) AF: 0.00183 AC: 28 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4826

European-Finnish (FIN) AF: 0.00772 AC: 82 AN: 10628

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

European-Non Finnish (NFE) AF: 0.00453 AC: 308 AN: 68026

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.00367 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Mitochondrial DNA depletion syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-2.5
Mutation Taster		=300/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs567251538; hg19: chr2-74153976;