17-62479511-T-TGGGGCCG

Variant names:

• chr17-62479511-T-TGGGGCCG
• rs1237399626
• NM_006852.6:c.-6+223_-6+229dupGGGCCGG

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 8P and 9B. PVS1 BP6 BS1 BS2

The NM_001375269.1(TLK2):​c.36_42dupGGGCCGG​(p.Arg15GlyfsTer41) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000343 in 151,816 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: 𝑓 0.00034 (0 hom., cov: 32)
• Consequence: TLK2 NM_001375269.1 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 1.05
• 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: Likely_benign. The variant received -1 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 73 pathogenic variants in the truncated region.
• BP6: Variant 17-62479511-T-TGGGGCCG is Benign according to our data. Variant chr17-62479511-T-TGGGGCCG is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1694856.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000343 (52/151816) while in subpopulation EAS AF = 0.0053 (27/5094). AF 95% confidence interval is 0.00374. There are 0 homozygotes in GnomAd4. There are 31 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 52 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001375269.1. 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.-6+223_-6+229dupGGGCCGG		intron	N/A	NP_006843.2
	TLK2	NM_001375269.1		c.36_42dupGGGCCGG	p.Arg15GlyfsTer41	frameshift	Exon 1 of 21	NP_001362198.1
	TLK2	NM_001284333.3		c.-3+223_-3+229dupGGGCCGG		intron	N/A	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.-6+223_-6+229dupGGGCCGG		intron	N/A	ENSP00000275780.7	Q86UE8-2
	TLK2	ENST00000326270.13	TSL:1	c.-3+223_-3+229dupGGGCCGG		intron	N/A	ENSP00000316512.9	Q86UE8-1
	TLK2	ENST00000343388.11	TSL:1	c.-6+223_-6+229dupGGGCCGG		intron	N/A	ENSP00000340800.7	Q86UE8-3

Frequencies

GnomAD3 genomes AF: 0.000343 AC: 52 AN: 151704 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00528

Gnomad SAS AF: 0.00187

Gnomad FIN AF: 0.000472

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000884

Gnomad OTH AF: 0.00144

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

GnomAD4 genome AF: 0.000343 AC: 52 AN: 151816 Hom.: 0 Cov.: 32 AF XY: 0.000418 AC XY: 31 AN XY: 74232

African (AFR) AF: 0.00 AC: 0 AN: 41442

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.000577 AC: 2 AN: 3466

East Asian (EAS) AF: 0.00530 AC: 27 AN: 5094

South Asian (SAS) AF: 0.00187 AC: 9 AN: 4812

European-Finnish (FIN) AF: 0.000472 AC: 5 AN: 10582

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.0000885 AC: 6 AN: 67830

Other (OTH) AF: 0.00142 AC: 3 AN: 2106

Alfa AF: 0.00 Hom.: 0

Asia WGS AF: 0.00925 AC: 32 AN: 3474

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Intellectual disability, autosomal dominant 57 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.0
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs1237399626; hg19: chr17-60556872;