rs16956600

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr16-66512079-C-A
• chr16-66512079-C-G
• chr16-66512079-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP6_Moderate

The NM_004614.5(TK2):​c.700-13G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000096 in 1,458,820 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: TK2 NM_004614.5 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 16-66512079-C-A is Benign according to our data. Variant chr16-66512079-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 3005318.Status of the report is criteria_provided_single_submitter, 1 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.700-13G>T		intron	N/A	NP_004605.4
	TK2	NM_001172645.2		c.646-13G>T		intron	N/A	NP_001166116.1
	TK2	NM_001172644.2		c.625-13G>T		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>T		intron	N/A	ENSP00000440898.2
	TK2	ENST00000451102.7	TSL:1	c.607-13G>T		intron	N/A	ENSP00000414334.4
	TK2	ENST00000527284.6	TSL:1	c.562-13G>T		intron	N/A	ENSP00000435312.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000960 AC: 14 AN: 1458820 Hom.: 0 Cov.: 28 AF XY: 0.00000689 AC XY: 5 AN XY: 725986

African (AFR) AF: 0.00 AC: 0 AN: 33432

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39686

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86220

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00000631 AC: 7 AN: 1109180

Other (OTH) AF: 0.0000166 AC: 1 AN: 60288

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	12
DANN	Benign	0.78
PhyloP100		1.3
PromoterAI		0.0028	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.22		Position offset: -13

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs16956600; hg19: chr16-66545982;