rs201904720

Variant names:

• chr16-66549940-G-A
• rs201904720
• NM_004614.5:c.122C>T

Your query was ambiguous. Multiple possible variants found:

• chr16-66549940-G-A
• chr16-66549940-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004614.5(TK2):​c.122C>T​(p.Pro41Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000148 in 1,353,902 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P41H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 8.3e-7 (0 hom.)
• Consequence: TK2 NM_004614.5 missense, splice_region
• Scores: Splicing: ADA: 0.2141
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.160
• Publications: 4 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: PanelApp Australia, Orphanet, Labcorp Genetics (formerly Invitae), G2P
• autosomal recessive progressive external ophthalmoplegia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000261519 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25608104).

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.122C>T	p.Pro41Leu	missense splice_region	Exon 1 of 10	NP_004605.4
	TK2	NM_001172645.2		c.122C>T	p.Pro41Leu	missense splice_region	Exon 1 of 9	NP_001166116.1	O00142-4
	TK2	NM_001172644.2		c.122C>T	p.Pro41Leu	missense splice_region	Exon 1 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.122C>T	p.Pro41Leu	missense splice_region	Exon 1 of 10	ENSP00000440898.2	O00142-1
	TK2	ENST00000527284.6	TSL:1	c.65C>T	p.Pro22Leu	missense splice_region	Exon 1 of 9	ENSP00000435312.2	A0A7P0PE46
	TK2	ENST00000451102.7	TSL:1	c.31+313C>T		intron	N/A	ENSP00000414334.4	O00142-2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152182 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 8.32e-7 AC: 1 AN: 1201720 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 582416

African (AFR) AF: 0.00 AC: 0 AN: 24076

American (AMR) AF: 0.00 AC: 0 AN: 10896

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16230

East Asian (EAS) AF: 0.00 AC: 0 AN: 28626

South Asian (SAS) AF: 0.00 AC: 0 AN: 46010

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29552

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3338

European-Non Finnish (NFE) AF: 0.00000101 AC: 1 AN: 993694

Other (OTH) AF: 0.00 AC: 0 AN: 49298

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152182 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74342

African (AFR) AF: 0.00 AC: 0 AN: 41462

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2090

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	9.4
DANN	Uncertain	0.99
DEOGEN2	Benign	0.33	T
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.72	T
M_CAP	Pathogenic	0.78	D
MetaRNN	Benign	0.26	T
MetaSVM	Uncertain	0.33	D
MutationAssessor	Benign	1.7	L
PhyloP100		0.16
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.76	N
REVEL	Benign	0.27
Sift	Uncertain	0.0070	D
Sift4G	Benign	0.25	T
Polyphen		0.035	B
Vest4		0.11
MutPred		0.28		Loss of glycosylation at P83 (P = 0.0062)
MVP		0.91
MPC		0.36
ClinPred		0.97	D
GERP RS		-0.044
PromoterAI		-0.0080	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.054
gMVP		0.48

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.21
dbscSNV1_RF	Benign	0.38
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: rs201904720; hg19: chr16-66583843;