rs12451705

Variant names:

• chr17-62579973-C-T
• rs12451705
• NM_006852.6:c.1287-138C>T

Variant summary

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

The NM_006852.6(TLK2):​c.1287-138C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.506 in 608,284 control chromosomes in the GnomAD database, including 83,953 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 0.43 (16821 hom., cov: 32)
  • Exomes 𝑓: 0.53 (67132 hom.)
• Consequence: TLK2 NM_006852.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.899
• Publications: 9 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: AD, SD Classification: DEFINITIVE, STRONG Submitted by: Illumina, Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.686 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006852.6. 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
	TLK2	NM_006852.6	MANE Select	c.1287-138C>T		intron	N/A	NP_006843.2
	TLK2	NM_001284333.3		c.1353-138C>T		intron	N/A	NP_001271262.1	Q86UE8-1
	TLK2	NM_001375269.1		c.1329-138C>T		intron	N/A	NP_001362198.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TLK2	ENST00000346027.10	TSL:1 MANE Select	c.1287-138C>T		intron	N/A	ENSP00000275780.7	Q86UE8-2
	TLK2	ENST00000326270.13	TSL:1	c.1353-138C>T		intron	N/A	ENSP00000316512.9	Q86UE8-1
	TLK2	ENST00000343388.11	TSL:1	c.1191-138C>T		intron	N/A	ENSP00000340800.7	Q86UE8-3

Frequencies

GnomAD3 genomes AF: 0.426 AC: 64762 AN: 151876 Hom.: 16822 Cov.: 32

Gnomad AFR AF: 0.124

Gnomad AMI AF: 0.629

Gnomad AMR AF: 0.443

Gnomad ASJ AF: 0.487

Gnomad EAS AF: 0.706

Gnomad SAS AF: 0.438

Gnomad FIN AF: 0.616

Gnomad MID AF: 0.446

Gnomad NFE AF: 0.549

Gnomad OTH AF: 0.446

GnomAD4 exome AF: 0.533 AC: 243031 AN: 456288 Hom.: 67132 AF XY: 0.530 AC XY: 127391 AN XY: 240142

African (AFR) AF: 0.120 AC: 1439 AN: 11974

American (AMR) AF: 0.446 AC: 7712 AN: 17292

Ashkenazi Jewish (ASJ) AF: 0.500 AC: 6606 AN: 13220

East Asian (EAS) AF: 0.664 AC: 19365 AN: 29152

South Asian (SAS) AF: 0.438 AC: 16617 AN: 37966

European-Finnish (FIN) AF: 0.593 AC: 21542 AN: 36330

Middle Eastern (MID) AF: 0.484 AC: 1708 AN: 3528

European-Non Finnish (NFE) AF: 0.552 AC: 155283 AN: 281472

Other (OTH) AF: 0.503 AC: 12759 AN: 25354

GnomAD4 genome AF: 0.426 AC: 64764 AN: 151996 Hom.: 16821 Cov.: 32 AF XY: 0.432 AC XY: 32094 AN XY: 74278

African (AFR) AF: 0.124 AC: 5126 AN: 41478

American (AMR) AF: 0.444 AC: 6776 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.487 AC: 1689 AN: 3470

East Asian (EAS) AF: 0.705 AC: 3646 AN: 5172

South Asian (SAS) AF: 0.438 AC: 2108 AN: 4814

European-Finnish (FIN) AF: 0.616 AC: 6493 AN: 10538

Middle Eastern (MID) AF: 0.435 AC: 127 AN: 292

European-Non Finnish (NFE) AF: 0.549 AC: 37296 AN: 67948

Other (OTH) AF: 0.441 AC: 931 AN: 2112

Alfa AF: 0.504 Hom.: 44123

Bravo AF: 0.402

Asia WGS AF: 0.485 AC: 1689 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	4.0
DANN	Benign	0.47
PhyloP100		-0.90
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: rs12451705; hg19: chr17-60657334; COSMIC: COSV107361309; COSMIC: COSV107361309;