Genetic Variant TLK2:c.-13_-8delGGCGGC (chr17-62479268-AGCGGCG-A) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1BS2

The NM_006852.6(TLK2):c.-13_-8delGGCGGC variant causes a splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00014 in 150,516 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 0.00014 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TLK2
NM_006852.6 splice_region

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.27

Publications

0 publications found

Variant links:

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

TLK2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00014 (21/150516) while in subpopulation AFR AF = 0.00039 (16/40978). AF 95% confidence interval is 0.000244. 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 21 AD,SD 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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TLK2	NM_006852.6	MANE Select	c.-13_-8delGGCGGC	splice_region	Exon 1 of 22	NP_006843.2
TLK2	NM_006852.6	MANE Select	c.-13_-8delGGCGGC	5_prime_UTR	Exon 1 of 22	NP_006843.2
TLK2	NM_001284333.3		c.-10_-5delGGCGGC	splice_region	Exon 1 of 23	NP_001271262.1	Q86UE8-1

Ensembl Transcripts

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

Frequencies

GnomAD3 genomes

AF:

0.000140

AC:

AN:

150516

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000390

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000967

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000445

Gnomad OTH

AF:

0.000482

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

15940

Hom.:

AF XY:

0.00

AC XY:

AN XY:

11902

African (AFR)

AF:

0.00

AC:

AN:

182

American (AMR)

AF:

0.00

AC:

AN:

172

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

108

East Asian (EAS)

AF:

0.00

AC:

AN:

544

South Asian (SAS)

AF:

0.00

AC:

AN:

1288

European-Finnish (FIN)

AF:

0.00

AC:

AN:

154

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

12838

Other (OTH)

AF:

0.00

AC:

AN:

598

GnomAD4 genome

AF:

0.000140

AC:

AN:

150516

Hom.:

Cov.:

AF XY:

0.000109

AC XY:

AN XY:

73456

show subpopulations

African (AFR)

AF:

0.000390

AC:

AN:

40978

American (AMR)

AF:

0.00

AC:

AN:

15186

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3450

East Asian (EAS)

AF:

0.00

AC:

AN:

5052

South Asian (SAS)

AF:

0.00

AC:

AN:

4804

European-Finnish (FIN)

AF:

0.0000967

AC:

AN:

10346

Middle Eastern (MID)

AF:

0.00

AC:

AN:

310

European-Non Finnish (NFE)

AF:

0.0000445

AC:

AN:

67416

Other (OTH)

AF:

0.000482

AC:

AN:

2074

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.000128

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.3

Splicing

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

Publications

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17-62479268-AGCGGCGGCGGCG-AGCGGCG

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over