ENST00000569718.6:c.-351-89G>C

Variant names:

• chr16-66551807-C-G
• rs725131
• ENST00000569718.6:c.-351-89G>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 15 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

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TK2	ENST00000569718.6	c.-351-89G>C		intron_variant	Intron 1 of 9	1		ENSP00000464313.2
TK2	ENST00000678015.1	c.-563G>C		5_prime_UTR_variant	Exon 1 of 10			ENSP00000502959.1
TK2	ENST00000678297.1	c.-488G>C		5_prime_UTR_variant	Exon 1 of 9			ENSP00000503472.1

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

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 12

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.182 AC: 4 AN: 22

Other (OTH) AC: 0 AN: 0

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

African (AFR) AF: 0.525 AC: 21781 AN: 41460

American (AMR) AF: 0.248 AC: 3789 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.110 AC: 382 AN: 3472

East Asian (EAS) AF: 0.293 AC: 1514 AN: 5176

South Asian (SAS) AF: 0.218 AC: 1049 AN: 4818

European-Finnish (FIN) AF: 0.0962 AC: 1020 AN: 10602

Middle Eastern (MID) AF: 0.134 AC: 39 AN: 292

European-Non Finnish (NFE) AF: 0.115 AC: 7791 AN: 67998

Other (OTH) AF: 0.207 AC: 438 AN: 2112

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
PhyloP100		0.28
PromoterAI		0.017	Neutral

Splicing

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

Other links and lift over

dbSNP: rs725131; hg19: chr16-66585710;