rs733025

Variant names:

• chr17-62458475-G-A
• rs733025
• ENST00000582809.5:c.-886G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000582809.5(TLK2):​c.-886G>A variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.265 in 150,888 control chromosomes in the GnomAD database, including 5,461 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.26 (5461 hom., cov: 33)
• Consequence: TLK2 ENST00000582809.5 upstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.914
• Publications: 5 publications found

Genes affected

TLK2 (HGNC:11842): (tousled like kinase 2) This gene encodes a nuclear serine/threonine kinase that was first identified in Arabidopsis. The encoded protein is thought to function in the regulation of chromatin assembly in the S phase of the cell cycle by regulating the levels of a histone H3/H4 chaperone. This protein is associated with double-strand break repair of DNA damage caused by radiation. Pseudogenes of this gene are present on chromosomes 10 and 17. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Sep 2013]

TLK2 Gene-Disease associations (from GenCC):

• intellectual disability, autosomal dominant 57

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Illumina, Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia

LOC112268200 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.353 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LOC112268200	XR_002958142.2	n.-183G>A		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TLK2	ENST00000582809.5	c.-886G>A		upstream_gene_variant		1		ENSP00000463595.1

Frequencies

GnomAD3 genomes AF: 0.265 AC: 39908 AN: 150768 Hom.: 5458 Cov.: 33

Gnomad AFR AF: 0.105

Gnomad AMI AF: 0.272

Gnomad AMR AF: 0.362

Gnomad ASJ AF: 0.381

Gnomad EAS AF: 0.191

Gnomad SAS AF: 0.316

Gnomad FIN AF: 0.325

Gnomad MID AF: 0.314

Gnomad NFE AF: 0.327

Gnomad OTH AF: 0.282

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.265 AC: 39921 AN: 150888 Hom.: 5461 Cov.: 33 AF XY: 0.265 AC XY: 19517 AN XY: 73698

African (AFR) AF: 0.105 AC: 4346 AN: 41482

American (AMR) AF: 0.361 AC: 5446 AN: 15092

Ashkenazi Jewish (ASJ) AF: 0.381 AC: 1301 AN: 3416

East Asian (EAS) AF: 0.192 AC: 990 AN: 5166

South Asian (SAS) AF: 0.315 AC: 1503 AN: 4768

European-Finnish (FIN) AF: 0.325 AC: 3405 AN: 10478

Middle Eastern (MID) AF: 0.312 AC: 91 AN: 292

European-Non Finnish (NFE) AF: 0.327 AC: 21993 AN: 67206

Other (OTH) AF: 0.288 AC: 600 AN: 2084

Alfa AF: 0.291 Hom.: 772

Bravo AF: 0.268

Asia WGS AF: 0.288 AC: 1000 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.18
DANN	Benign	0.63
PhyloP100		-0.91
PromoterAI		0.00090	Neutral

Splicing

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

Other links and lift over

dbSNP: rs733025; hg19: chr17-60535836;