17-62523126-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BS1 BS2

The NM_006852.6(TLK2):c.224-8A>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00024 in 1,588,618 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00033 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00023 (1 hom.)
• Consequence: TLK2 NM_006852.6 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.003138
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.697

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 17-62523126-A-G is Benign according to our data. Variant chr17-62523126-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 2648028.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000328 (50/152256) while in subpopulation AMR AF= 0.00144 (22/15292). AF 95% confidence interval is 0.000973. There are 1 homozygotes in gnomad4. There are 24 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 50 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TLK2	NM_006852.6	c.224-8A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000346027.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TLK2	ENST00000346027.10	c.224-8A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_006852.6	P3

Frequencies

GnomAD3 genomes AF: 0.000329 AC: 50 AN: 152138 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.000267 AC: 59 AN: 220622 Hom.: 0 AF XY: 0.000250 AC XY: 30 AN XY: 120228

Gnomad AFR exome AF: 0.0000665

Gnomad AMR exome AF: 0.000429

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000809

Gnomad FIN exome AF: 0.0000481

Gnomad NFE exome AF: 0.000391

Gnomad OTH exome AF: 0.000580

GnomAD4 exome AF: 0.000230 AC: 331 AN: 1436362 Hom.: 1 Cov.: 30 AF XY: 0.000237 AC XY: 169 AN XY: 714378

Gnomad4 AFR exome AF: 0.000412

Gnomad4 AMR exome AF: 0.000467

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000369

Gnomad4 FIN exome AF: 0.0000189

Gnomad4 NFE exome AF: 0.000219

Gnomad4 OTH exome AF: 0.000389

GnomAD4 genome AF: 0.000328 AC: 50 AN: 152256 Hom.: 1 Cov.: 32 AF XY: 0.000322 AC XY: 24 AN XY: 74474

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.00144

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000246 Hom.: 0

Bravo AF: 0.000446

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2024

TLK2: BP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
Cadd	Benign	14
Dann	Benign	0.86

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0031
dbscSNV1_RF	Benign	0.0060
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

Publications

LitVar

Other links and lift over

dbSNP: rs199986685; hg19: chr17-60600487;