16-66531432-G-C

Variant names:

• chr16-66531432-G-C
• NM_004614.5:c.323C>G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_004614.5(TK2):​c.323C>G​(p.Thr108Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TK2 NM_004614.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.48

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a chain Thymidine kinase 2, mitochondrial (size 231) in uniprot entity KITM_HUMAN there are 9 pathogenic changes around while only 1 benign (90%) in NM_004614.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.826

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TK2	NM_004614.5	c.323C>G	p.Thr108Arg	missense_variant	Exon 5 of 10	ENST00000544898.6	NP_004605.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TK2	ENST00000544898.6	c.323C>G	p.Thr108Arg	missense_variant	Exon 5 of 10	1	NM_004614.5	ENSP00000440898.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	29
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.94	D;.;D;.;.;.;.;D;.;.;.;D;D
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.96	D;D;.;D;.;D;D;D;.;D;D;D;D
M_CAP	Pathogenic	0.53	D
MetaRNN	Pathogenic	0.83	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.87	D
MutationAssessor	Pathogenic	3.0	M;.;M;.;.;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-4.0	.;.;.;.;D;D;D;D;D;.;.;.;.
REVEL	Pathogenic	0.83
Sift	Benign	0.059	.;.;.;.;T;T;D;D;T;.;.;.;.
Sift4G	Uncertain	0.034	D;D;D;D;T;D;D;D;T;D;T;.;.
Polyphen		0.99	D;.;D;.;.;B;.;.;.;.;.;.;.
Vest4		0.89
MutPred		0.58		.;.;.;Gain of MoRF binding (P = 0.0054);.;.;.;.;.;.;.;.;.;
MVP		0.96
MPC		1.2
ClinPred		0.99	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.86
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-66565335;