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):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• intellectual disability, autosomal dominant 57

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

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000582809.5. 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
There are no transcript annotations for this variant.

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TLK2	ENST00000582809.5	TSL:1	c.-886G>A		upstream_gene	N/A	ENSP00000463595.1	J3QLK5

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 v4.9

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs733025;

hg19: chr17-60535836;