NM_006852.6:c.-13_-8dupGGCGGC

Variant names:

• chr17-62479268-A-AGCGGCG
• rs768508482
• NM_006852.6:c.-13_-8dupGGCGGC

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_006852.6(TLK2):​c.-13_-8dupGGCGGC variant causes a splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000114 in 166,458 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: TLK2 NM_006852.6 splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.343
• Publications: 0 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 -8 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000113 (17/150516) while in subpopulation AFR AF = 0.000293 (12/40978). AF 95% confidence interval is 0.000168. There are 0 homozygotes in GnomAd4. There are 8 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 17 AD gene.

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.-13_-8dupGGCGGC		splice_region	Exon 1 of 22	NP_006843.2
	TLK2	NM_006852.6	MANE Select	c.-13_-8dupGGCGGC		5_prime_UTR	Exon 1 of 22	NP_006843.2
	TLK2	NM_001284333.3		c.-10_-5dupGGCGGC		splice_region	Exon 1 of 23	NP_001271262.1	Q86UE8-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TLK2	ENST00000346027.10	TSL:1 MANE Select	c.-13_-8dupGGCGGC		splice_region	Exon 1 of 22	ENSP00000275780.7	Q86UE8-2
	TLK2	ENST00000326270.13	TSL:1	c.-10_-5dupGGCGGC		splice_region	Exon 1 of 23	ENSP00000316512.9	Q86UE8-1
	TLK2	ENST00000343388.11	TSL:1	c.-13_-8dupGGCGGC		splice_region	Exon 1 of 21	ENSP00000340800.7	Q86UE8-3

Frequencies

GnomAD3 genomes AF: 0.000113 AC: 17 AN: 150516 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000293

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000132

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.0000967

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000148

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000125 AC: 2 AN: 15942 Hom.: 0 Cov.: 0 AF XY: 0.000168 AC XY: 2 AN XY: 11904

African (AFR) AF: 0.00 AC: 0 AN: 182

American (AMR) AF: 0.00 AC: 0 AN: 172

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 108

East Asian (EAS) AF: 0.00 AC: 0 AN: 544

South Asian (SAS) AF: 0.00 AC: 0 AN: 1288

European-Finnish (FIN) AF: 0.00649 AC: 1 AN: 154

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 56

European-Non Finnish (NFE) AF: 0.0000779 AC: 1 AN: 12840

Other (OTH) AF: 0.00 AC: 0 AN: 598

GnomAD4 genome AF: 0.000113 AC: 17 AN: 150516 Hom.: 0 Cov.: 31 AF XY: 0.000109 AC XY: 8 AN XY: 73456

African (AFR) AF: 0.000293 AC: 12 AN: 40978

American (AMR) AF: 0.000132 AC: 2 AN: 15186

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3450

East Asian (EAS) AF: 0.00 AC: 0 AN: 5052

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4804

European-Finnish (FIN) AF: 0.0000967 AC: 1 AN: 10346

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 310

European-Non Finnish (NFE) AF: 0.0000148 AC: 1 AN: 67416

Other (OTH) AF: 0.00 AC: 0 AN: 2074

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000567

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.34

Splicing

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

Other links and lift over

dbSNP: rs768508482; hg19: chr17-60556629;