NM_004614.5:c.700-13G>A

Variant names:

• chr16-66512079-C-T
• rs16956600
• NM_004614.5:c.700-13G>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_004614.5(TK2):​c.700-13G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0955 in 1,610,742 control chromosomes in the GnomAD database, including 8,333 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1337 hom., cov: 33)
  • Exomes 𝑓: 0.093 (6996 hom.)
• Consequence: TK2 NM_004614.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.26
• Publications: 12 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: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 16-66512079-C-T is Benign according to our data. Variant chr16-66512079-C-T is described in ClinVar as Benign. ClinVar VariationId is 137664.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.19 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.700-13G>A		intron	N/A	NP_004605.4
	TK2	NM_001172645.2		c.646-13G>A		intron	N/A	NP_001166116.1
	TK2	NM_001172644.2		c.625-13G>A		intron	N/A	NP_001166115.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TK2	ENST00000544898.6	TSL:1 MANE Select	c.700-13G>A		intron	N/A	ENSP00000440898.2
	TK2	ENST00000451102.7	TSL:1	c.607-13G>A		intron	N/A	ENSP00000414334.4
	TK2	ENST00000527284.6	TSL:1	c.562-13G>A		intron	N/A	ENSP00000435312.2

Frequencies

GnomAD3 genomes AF: 0.121 AC: 18344 AN: 152080 Hom.: 1339 Cov.: 33

Gnomad AFR AF: 0.194

Gnomad AMI AF: 0.114

Gnomad AMR AF: 0.129

Gnomad ASJ AF: 0.0729

Gnomad EAS AF: 0.164

Gnomad SAS AF: 0.112

Gnomad FIN AF: 0.0481

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0858

Gnomad OTH AF: 0.110

GnomAD2 exomes AF: 0.113 AC: 28176 AN: 248988 AF XY: 0.109

Gnomad AFR exome AF: 0.195

Gnomad AMR exome AF: 0.175

Gnomad ASJ exome AF: 0.0749

Gnomad EAS exome AF: 0.168

Gnomad FIN exome AF: 0.0503

Gnomad NFE exome AF: 0.0884

Gnomad OTH exome AF: 0.107

GnomAD4 exome AF: 0.0928 AC: 135414 AN: 1458544 Hom.: 6996 Cov.: 28 AF XY: 0.0927 AC XY: 67255 AN XY: 725878

African (AFR) AF: 0.201 AC: 6710 AN: 33428

American (AMR) AF: 0.174 AC: 7763 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0743 AC: 1940 AN: 26116

East Asian (EAS) AF: 0.152 AC: 6020 AN: 39680

South Asian (SAS) AF: 0.112 AC: 9682 AN: 86216

European-Finnish (FIN) AF: 0.0535 AC: 2858 AN: 53410

Middle Eastern (MID) AF: 0.0889 AC: 512 AN: 5760

European-Non Finnish (NFE) AF: 0.0846 AC: 93846 AN: 1108944

Other (OTH) AF: 0.101 AC: 6083 AN: 60272

GnomAD4 genome AF: 0.121 AC: 18358 AN: 152198 Hom.: 1337 Cov.: 33 AF XY: 0.118 AC XY: 8793 AN XY: 74404

African (AFR) AF: 0.194 AC: 8037 AN: 41510

American (AMR) AF: 0.130 AC: 1981 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0729 AC: 253 AN: 3470

East Asian (EAS) AF: 0.164 AC: 846 AN: 5172

South Asian (SAS) AF: 0.112 AC: 541 AN: 4824

European-Finnish (FIN) AF: 0.0481 AC: 510 AN: 10596

Middle Eastern (MID) AF: 0.0714 AC: 21 AN: 294

European-Non Finnish (NFE) AF: 0.0857 AC: 5831 AN: 68014

Other (OTH) AF: 0.111 AC: 234 AN: 2114

Alfa AF: 0.0971 Hom.: 3501

Bravo AF: 0.133

Asia WGS AF: 0.152 AC: 529 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Mitochondrial DNA depletion syndrome, myopathic form (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	12
DANN	Benign	0.77
PhyloP100		1.3
PromoterAI		-0.029	Neutral
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs16956600; hg19: chr16-66545982; COSMIC: COSV55283774; COSMIC: COSV55283774;