chr16-66509747-A-G

Variant names:

• chr16-66509747-A-G
• rs3743712
• NM_004614.5:c.*2221T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -4.88
• 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: Labcorp Genetics (formerly Invitae), G2P, Orphanet
• autosomal recessive progressive external ophthalmoplegia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000260851 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 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 VariationId is 320127.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.314 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TK2	NM_004614.5	MANE Select	c.*2221T>C		3_prime_UTR	Exon 10 of 10	NP_004605.4
	TK2	NM_001172645.2		c.*2221T>C		3_prime_UTR	Exon 9 of 9	NP_001166116.1	O00142-4
	TK2	NM_001172644.2		c.*2221T>C		3_prime_UTR	Exon 9 of 9	NP_001166115.1	O00142-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TK2	ENST00000544898.6	TSL:1 MANE Select	c.*2221T>C		3_prime_UTR	Exon 10 of 10	ENSP00000440898.2	O00142-1
	TK2	ENST00000451102.7	TSL:1	c.*2221T>C		3_prime_UTR	Exon 10 of 10	ENSP00000414334.4	O00142-2
	TK2	ENST00000299697.12	TSL:1	c.*2221T>C		3_prime_UTR	Exon 9 of 9	ENSP00000299697.9	A0A7P0MLU2

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

African (AFR) AF: 0.300 AC: 3 AN: 10

American (AMR) AF: 0.00 AC: 0 AN: 10

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 4

East Asian (EAS) AF: 0.208 AC: 5 AN: 24

South Asian (SAS) AF: 0.250 AC: 2 AN: 8

European-Finnish (FIN) AF: 0.0536 AC: 3 AN: 56

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4

European-Non Finnish (NFE) AF: 0.0257 AC: 11 AN: 428

Other (OTH) AF: 0.0600 AC: 3 AN: 50

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

African (AFR) AF: 0.319 AC: 13231 AN: 41500

American (AMR) AF: 0.100 AC: 1530 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0222 AC: 77 AN: 3468

East Asian (EAS) AF: 0.160 AC: 828 AN: 5170

South Asian (SAS) AF: 0.179 AC: 862 AN: 4822

European-Finnish (FIN) AF: 0.0511 AC: 542 AN: 10616

Middle Eastern (MID) AF: 0.0616 AC: 18 AN: 292

European-Non Finnish (NFE) AF: 0.0375 AC: 2550 AN: 68010

Other (OTH) AF: 0.100 AC: 212 AN: 2110

Alfa AF: 0.0608 Hom.: 1455

Bravo AF: 0.140

Asia WGS AF: 0.162 AC: 561 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Mitochondrial DNA depletion syndrome, myopathic form (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.054
DANN	Benign	0.29
PhyloP100		-4.9
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3743712; hg19: chr16-66543650;