Variant 2-73957134-AAG-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_080916.3(DGUOK):c.605_606del(p.Arg202ThrfsTer13) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000205 in 1,461,476 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

DGUOK
NM_080916.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 6.87

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:

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

DGUOK-AS1 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 2-73957134-AAG-A is Pathogenic according to our data. Variant chr2-73957134-AAG-A is described in ClinVar as [Pathogenic]. Clinvar id is 214288.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DGUOK	NM_080916.3 linkuse as main transcript	c.605_606del	p.Arg202ThrfsTer13	frameshift_variant	5/7	ENST00000264093.9	NP_550438.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DGUOK	ENST00000264093.9 linkuse as main transcript	c.605_606del	p.Arg202ThrfsTer13	frameshift_variant	5/7	1	NM_080916.3	ENSP00000264093	P1	Q16854-1
DGUOK-AS1	ENST00000667561.3 linkuse as main transcript	n.308-9201_308-9200del		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251360

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135846

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461476

Hom.:

AF XY:

0.00000275

AC XY:

AN XY:

727076

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Mitochondrial DNA depletion syndrome 3 (hepatocerebral type)

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 14, 2017	The p.Arg202ThrfsX13 (NM_080916.2 c.605_606delGA) variant in DGUOK has been repo rted in 3 compound heterozygous individuals with clinical features of Deoxyguano sine kinase deficiency or mitochondrial DNA depletion syndrome (Ronchi 2012 and Alberio 2007). This variant has also been reported in ClinVar (Variation ID#2142 88) as pathogenic by 1 laboratory. This variant has been identified in 0.002% (2 /11,2150) of European chromosomes by the Genome Aggregation Database (gnomAD, ht tp://gnomad.broadinstitute.org). Although this variant has been seen in the gene ral population, its frequency is low enough to be consistent with a recessive ca rrier frequency. This variant is predicted to cause a frameshift, which alters t he protein?s amino acid sequence beginning at position 202 and leads to a premat ure termination codon 13 amino acids downstream. This alteration is then predict ed to lead to a truncated or absent protein. Biallelic loss of function of funct ion of the DGUOK gene is an established disease mechanism in Deoxyguanosine kina se deficiency. In summary, this variant meets criteria to be classified as patho genic for Deoxyguanosine kinase deficiency in an autosomal recessive manner base d upon its occurrence in patients and predicted null effect. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 18, 2016	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 16, 2024	This sequence change creates a premature translational stop signal (p.Arg202Thrfs*13) in the DGUOK gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DGUOK are known to be pathogenic (PMID: 18205204). This variant is present in population databases (no rsID available, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with DGUOK-related conditions (PMID: 17280874). This variant is also known as 603-604 delGA (K201fs214X). ClinVar contains an entry for this variant (Variation ID: 214288). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 01, 2019	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 30609409, 17280874, 18205204, 23043144, 24478274) -

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 4

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 18, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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