Genetic Variant TLK2:c.224-8A>G (chr17-62523126-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_ModerateBP6_ModerateBS1BS2

The NM_006852.6(TLK2):c.224-8A>G variant causes a splice region, 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, intron

Scores

Splicing: ADA: 0.003138

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.697

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 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check.

BS2

High AC in GnomAd4 at 50 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TLK2	NM_006852.6 link	c.224-8A>G		splice_region_variant, intron_variant	Intron 4 of 21	ENST00000346027.10	NP_006843.2	Q86UE8-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TLK2	ENST00000346027.10 link	c.224-8A>G		splice_region_variant, intron_variant	Intron 4 of 21	1	NM_006852.6	ENSP00000275780.7		Q86UE8-2

Frequencies

GnomAD3 genomes

AF:

0.000329

AC:

AN:

152138

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.000267

AC:

AN:

220622

AF XY:

0.000250

show subpopulations

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 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.:

Cov.:

AF XY:

0.000237

AC XY:

169

AN XY:

714378

show subpopulations

Gnomad4 AFR exome

AF:

0.000412

AC:

AN:

31568

Gnomad4 AMR exome

AF:

0.000467

AC:

AN:

36394

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

24718

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

39494

Gnomad4 SAS exome

AF:

0.0000369

AC:

AN:

81280

Gnomad4 FIN exome

AF:

0.0000189

AC:

AN:

52812

Gnomad4 NFE exome

AF:

0.000219

AC:

242

AN:

1105324

Gnomad4 Remaining exome

AF:

0.000389

AC:

AN:

59162

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome 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

GnomAD4 genome

AF:

0.000328

AC:

AN:

152256

Hom.:

Cov.:

AF XY:

0.000322

AC XY:

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.0000722

AC:

0.000072223

AN:

0.000072223

Gnomad4 AMR

AF:

0.00144

AC:

0.00143866

AN:

0.00143866

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00

AC:

AN:

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.000250

AC:

0.000249912

AN:

0.000249912

Gnomad4 OTH

AF:

0.00237

AC:

0.00236967

AN:

0.00236967

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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:

0.000246

Hom.:

Bravo

AF:

0.000446

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Apr 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TLK2: BP4 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.36

CADD

Benign

DANN

Benign

0.86

Mutation Taster

=100/0

polymorphism

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over