NM_004614.5:c.644T>C

Variant names:

• chr16-66513786-A-G
• rs281865497
• NM_004614.5:c.644T>C

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_004614.5(TK2):​c.644T>C​(p.Leu215Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,814 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L215I) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TK2 NM_004614.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 4.82
• Publications: 6 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: Pathogenic. The variant received 16 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_004614.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-66513787-G-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3897043.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.917
• PP5: Variant 16-66513786-A-G is Pathogenic according to our data. Variant chr16-66513786-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 2736362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.644T>C	p.Leu215Pro	missense	Exon 9 of 10	NP_004605.4
	TK2	NM_001172645.2		c.590T>C	p.Leu197Pro	missense	Exon 8 of 9	NP_001166116.1
	TK2	NM_001172644.2		c.569T>C	p.Leu190Pro	missense	Exon 8 of 9	NP_001166115.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TK2	ENST00000544898.6	TSL:1 MANE Select	c.644T>C	p.Leu215Pro	missense	Exon 9 of 10	ENSP00000440898.2
	TK2	ENST00000451102.7	TSL:1	c.551T>C	p.Leu184Pro	missense	Exon 9 of 10	ENSP00000414334.4
	TK2	ENST00000299697.12	TSL:1	c.476T>C	p.Leu159Pro	missense	Exon 8 of 9	ENSP00000299697.9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251252 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461814 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727206

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5720

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1112006

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Mitochondrial disease (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.59	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		4.8
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-6.2	D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.025	D
Polyphen		1.0	D
Vest4		0.91
MutPred		0.67		Loss of stability (P = 0.0272)
MVP		1.0
MPC		1.4
ClinPred		0.98	D
GERP RS		4.9
PromoterAI		-0.0049	Neutral
Varity_R		0.99
gMVP		0.87
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		1.0
SpliceAI score (max)		0.010		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: rs281865497; hg19: chr16-66547689;