16-66517207-G-C

Variant names:

• chr16-66517207-G-C
• rs137886900
• NM_004614.5:c.547C>G

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_004614.5(TK2):​c.547C>G​(p.Arg183Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000547 in 1,461,794 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R183Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: TK2 NM_004614.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 5.18
• Publications: 19 publications found

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]

TK2 Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• mitochondrial DNA depletion syndrome, myopathic form

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• autosomal recessive progressive external ophthalmoplegia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000260851 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_004614.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-66517207-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 38992.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.908
• PP5: Variant 16-66517207-G-C is Pathogenic according to our data. Variant chr16-66517207-G-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 38991.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004614.5. 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
	TK2	NM_004614.5	MANE Select	c.547C>G	p.Arg183Gly	missense	Exon 8 of 10	NP_004605.4
	TK2	NM_001172645.2		c.493C>G	p.Arg165Gly	missense	Exon 7 of 9	NP_001166116.1
	TK2	NM_001172644.2		c.472C>G	p.Arg158Gly	missense	Exon 7 of 9	NP_001166115.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TK2	ENST00000544898.6	TSL:1 MANE Select	c.547C>G	p.Arg183Gly	missense	Exon 8 of 10	ENSP00000440898.2
	TK2	ENST00000451102.7	TSL:1	c.454C>G	p.Arg152Gly	missense	Exon 8 of 10	ENSP00000414334.4
	TK2	ENST00000527284.6	TSL:1	c.490C>G	p.Arg164Gly	missense	Exon 8 of 9	ENSP00000435312.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000795 AC: 2 AN: 251488 AF XY: 0.00000736

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461794 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727206

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

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

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1111920

Other (OTH) AF: 0.0000166 AC: 1 AN: 60394

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.000218

EpiControl AF: 0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mitochondrial disease Pathogenic:1

Apr 10, 2025

Genomenon, Inc, Genomenon, Inc

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

TK2 Arg183Gly (c.547C>G) is a missense variant that changes the amino acid at residue 183 from Arginine to Glycine. It is also described as R152G and R225G in the literature. This variant has been observed in multiple probands affected with mitochondrial disease in the compound heterozygous state, with a pathogenic or likely pathogenic variant confirmed in trans in at least one proband (PMID:38544965;19125351;29602790;12655576). Experimental studies showed reduced activity, however, the significance of this finding remains unclear (19154348). This variant is not present at a significant frequency in gnomAD, and in silico models agree that this variant is possibly or probably damaging. In conclusion, we classify TK2 Arg183Gly (c.547C>G) as a likely pathogenic variant.

not provided Pathogenic:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 183 of the TK2 protein (p.Arg183Gly). This variant is present in population databases (rs137886900, gnomAD 0.002%). This missense change has been observed in individuals with TK2-related conditions (PMID: 12655576, 12682338, 29602790). This variant is also known as R152G. ClinVar contains an entry for this variant (Variation ID: 38991). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt TK2 protein function with a positive predictive value of 95%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the p.Arg183 amino acid residue in TK2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15907288, 18819985, 29602790). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.53	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		5.2
PrimateAI	Benign	0.27	T
PROVEAN	Pathogenic	-5.3	D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.99	D
Vest4		0.84
MutPred		0.70		Loss of glycosylation at P228 (P = 0.0836)
MVP		0.99
MPC		1.1
ClinPred		0.98	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		0.63
Mutation Taster		=0/100	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs137886900; hg19: chr16-66551110;