16-66548963-A-G

Variant names:

• chr16-66548963-A-G
• rs80083556
• NM_004614.5:c.156+15T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004614.5(TK2):​c.156+15T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0113 in 1,611,374 control chromosomes in the GnomAD database, including 1,765 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.060 (923 hom., cov: 32)
  • Exomes 𝑓: 0.0062 (842 hom.)
• Consequence: TK2 NM_004614.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.756
• Publications: 1 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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 16-66548963-A-G is Benign according to our data. Variant chr16-66548963-A-G is described in ClinVar as Benign. ClinVar VariationId is 137660.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.205 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TK2	NM_004614.5	MANE Select	c.156+15T>C		intron	N/A	NP_004605.4
	TK2	NM_001172645.2		c.156+15T>C		intron	N/A	NP_001166116.1
	TK2	NM_001172644.2		c.156+15T>C		intron	N/A	NP_001166115.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TK2	ENST00000544898.6	TSL:1 MANE Select	c.156+15T>C		intron	N/A	ENSP00000440898.2
	TK2	ENST00000451102.7	TSL:1	c.63+15T>C		intron	N/A	ENSP00000414334.4
	TK2	ENST00000527284.6	TSL:1	c.99+15T>C		intron	N/A	ENSP00000435312.2

Frequencies

GnomAD3 genomes AF: 0.0601 AC: 9145 AN: 152098 Hom.: 922 Cov.: 32

Gnomad AFR AF: 0.209

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0253

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.000735

Gnomad OTH AF: 0.0344

GnomAD2 exomes AF: 0.0154 AC: 3867 AN: 251302 AF XY: 0.0113

Gnomad AFR exome AF: 0.208

Gnomad AMR exome AF: 0.0103

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000686

Gnomad OTH exome AF: 0.00603

GnomAD4 exome AF: 0.00617 AC: 9003 AN: 1459158 Hom.: 842 Cov.: 29 AF XY: 0.00529 AC XY: 3839 AN XY: 726148

African (AFR) AF: 0.213 AC: 7103 AN: 33370

American (AMR) AF: 0.0111 AC: 495 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.000153 AC: 4 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39666

South Asian (SAS) AF: 0.000394 AC: 34 AN: 86192

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53400

Middle Eastern (MID) AF: 0.0101 AC: 58 AN: 5758

European-Non Finnish (NFE) AF: 0.000470 AC: 522 AN: 1109694

Other (OTH) AF: 0.0130 AC: 786 AN: 60270

GnomAD4 genome AF: 0.0602 AC: 9156 AN: 152216 Hom.: 923 Cov.: 32 AF XY: 0.0581 AC XY: 4327 AN XY: 74438

African (AFR) AF: 0.208 AC: 8642 AN: 41502

American (AMR) AF: 0.0252 AC: 385 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4820

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10622

Middle Eastern (MID) AF: 0.0103 AC: 3 AN: 292

European-Non Finnish (NFE) AF: 0.000735 AC: 50 AN: 68006

Other (OTH) AF: 0.0341 AC: 72 AN: 2112

Alfa AF: 0.0173 Hom.: 71

Bravo AF: 0.0671

Asia WGS AF: 0.0110 AC: 37 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	-0.67
CADD	Benign	12
DANN	Benign	0.89
PhyloP100		0.76
PromoterAI		-0.026	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs80083556; hg19: chr16-66582866;