16-66509747-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_004614.5(TK2):c.*2221T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.13 in 152,784 control chromosomes in the GnomAD database, including 2,445 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.13 (2441 hom., cov: 33)
  • Exomes 𝑓: 0.045 (4 hom.)
• Consequence: TK2 NM_004614.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -4.88

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BP6: Variant 16-66509747-A-G is Benign according to our data. Variant chr16-66509747-A-G is described in ClinVar as [Benign]. Clinvar id is 320127.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.314 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TK2	NM_004614.5	c.*2221T>C		3_prime_UTR_variant	10/10	ENST00000544898.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TK2	ENST00000544898.6	c.*2221T>C		3_prime_UTR_variant	10/10	1	NM_004614.5	P1
	ENST00000568560.1	n.311A>G		non_coding_transcript_exon_variant	1/2	5

Frequencies

GnomAD3 genomes AF: 0.131 AC: 19853 AN: 152072 Hom.: 2437 Cov.: 33

Gnomad AFR AF: 0.319

Gnomad AMI AF: 0.0406

Gnomad AMR AF: 0.100

Gnomad ASJ AF: 0.0222

Gnomad EAS AF: 0.160

Gnomad SAS AF: 0.179

Gnomad FIN AF: 0.0511

Gnomad MID AF: 0.0573

Gnomad NFE AF: 0.0375

Gnomad OTH AF: 0.101

GnomAD4 exome AF: 0.0455 AC: 27 AN: 594 Hom.: 4 Cov.: 0 AF XY: 0.0407 AC XY: 17 AN XY: 418

Gnomad4 AFR exome AF: 0.300

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.208

Gnomad4 SAS exome AF: 0.250

Gnomad4 FIN exome AF: 0.0536

Gnomad4 NFE exome AF: 0.0257

Gnomad4 OTH exome AF: 0.0600

GnomAD4 genome AF: 0.131 AC: 19887 AN: 152190 Hom.: 2441 Cov.: 33 AF XY: 0.132 AC XY: 9822 AN XY: 74422

Gnomad4 AFR AF: 0.319

Gnomad4 AMR AF: 0.100

Gnomad4 ASJ AF: 0.0222

Gnomad4 EAS AF: 0.160

Gnomad4 SAS AF: 0.179

Gnomad4 FIN AF: 0.0511

Gnomad4 NFE AF: 0.0375

Gnomad4 OTH AF: 0.100

Alfa AF: 0.0523 Hom.: 648

Bravo AF: 0.140

Asia WGS AF: 0.162 AC: 561 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Mitochondrial DNA depletion syndrome, myopathic form Benign:1

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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
Cadd	Benign	0.054
Dann	Benign	0.29

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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

Other links and lift over

dbSNP: rs3743712; hg19: chr16-66543650;