rs725131

Positions:

• chr16-66551807-C-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000569718.6(TK2):​c.-351-89G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.249 in 152,150 control chromosomes in the GnomAD database, including 7,212 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.25 (7212 hom., cov: 33)
  • Exomes 𝑓: 0.12 (0 hom.)
• Consequence: TK2 ENST00000569718.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.275

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.52 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TK2	ENST00000569718.6	c.-351-89G>C		intron_variant		1		ENSP00000464313
TK2	ENST00000678015.1	c.-563G>C		5_prime_UTR_variant	1/10			ENSP00000502959
TK2	ENST00000678297.1	c.-488G>C		5_prime_UTR_variant	1/9			ENSP00000503472

Frequencies

GnomAD3 genomes AF: 0.249 AC: 37886 AN: 151998 Hom.: 7192 Cov.: 33

Gnomad AFR AF: 0.525

Gnomad AMI AF: 0.169

Gnomad AMR AF: 0.248

Gnomad ASJ AF: 0.110

Gnomad EAS AF: 0.293

Gnomad SAS AF: 0.218

Gnomad FIN AF: 0.0962

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.115

Gnomad OTH AF: 0.208

GnomAD4 exome AF: 0.118 AC: 4 AN: 34 Hom.: 0 AF XY: 0.0625 AC XY: 1 AN XY: 16

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.182

GnomAD4 genome AF: 0.250 AC: 37957 AN: 152116 Hom.: 7212 Cov.: 33 AF XY: 0.248 AC XY: 18413 AN XY: 74374

Gnomad4 AFR AF: 0.525

Gnomad4 AMR AF: 0.248

Gnomad4 ASJ AF: 0.110

Gnomad4 EAS AF: 0.293

Gnomad4 SAS AF: 0.218

Gnomad4 FIN AF: 0.0962

Gnomad4 NFE AF: 0.115

Gnomad4 OTH AF: 0.207

Alfa AF: 0.185 Hom.: 570

Bravo AF: 0.276

Asia WGS AF: 0.271 AC: 941 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	5.5
DANN	Benign	0.56

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs725131; hg19: chr16-66585710;