rs187517309
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Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_004614.5(TK2):c.231+10C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00739 in 1,613,988 control chromosomes in the GnomAD database, including 75 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.0048 ( 5 hom., cov: 32)
Exomes 𝑓: 0.0077 ( 70 hom. )
Consequence
TK2
NM_004614.5 intron
NM_004614.5 intron
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.243
Genes affected
TK2 (HGNC:11831): (thymidine kinase 2) This gene encodes a deoxyribonucleoside kinase that specifically phosphorylates thymidine, deoxycytidine, and deoxyuridine. The encoded enzyme localizes to the mitochondria and is required for mitochondrial DNA synthesis. Mutations in this gene are associated with a myopathic form of mitochondrial DNA depletion syndrome. Alternate splicing results in multiple transcript variants encoding distinct isoforms, some of which lack transit peptide, so are not localized to mitochondria. [provided by RefSeq, Dec 2012]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -20 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.81).
BP6
?
Variant 16-66541869-G-A is Benign according to our data. Variant chr16-66541869-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 137668.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-66541869-G-A is described in Lovd as [Benign]. Variant chr16-66541869-G-A is described in Lovd as [Likely_benign].
BS1
?
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0048 (731/152266) while in subpopulation NFE AF= 0.0086 (585/68026). AF 95% confidence interval is 0.00802. There are 5 homozygotes in gnomad4. There are 302 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
High Homozygotes in GnomAd4 at 5 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TK2 | NM_004614.5 | c.231+10C>T | intron_variant | ENST00000544898.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TK2 | ENST00000544898.6 | c.231+10C>T | intron_variant | 1 | NM_004614.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00480 AC: 731AN: 152148Hom.: 5 Cov.: 32
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GnomAD3 exomes AF: 0.00521 AC: 1311AN: 251448Hom.: 13 AF XY: 0.00553 AC XY: 751AN XY: 135896
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GnomAD4 exome AF: 0.00766 AC: 11198AN: 1461722Hom.: 70 Cov.: 31 AF XY: 0.00770 AC XY: 5599AN XY: 727154
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GnomAD4 genome ? AF: 0.00480 AC: 731AN: 152266Hom.: 5 Cov.: 32 AF XY: 0.00406 AC XY: 302AN XY: 74442
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:11
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:4
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Mar 02, 2016 | - - |
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 25, 2019 | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
not specified Benign:3
Benign, criteria provided, single submitter | clinical testing | GeneDx | Jan 11, 2013 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Dec 31, 2019 | - - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Mitochondrial DNA depletion syndrome, myopathic form Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | Jul 08, 2016 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. - |
TK2-related disorder Benign:1
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | May 02, 2019 | This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Mitochondrial DNA depletion syndrome, myopathic form;C4310734:Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 3 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 21, 2021 | - - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at