chr17-62523136-A-C

Position:

• chr17-62523136-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_006852.6(TLK2):​c.226A>C​(p.Lys76Gln) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TLK2 NM_006852.6 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.51

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), TLK2. . Gene score misZ 4.4909 (greater than the threshold 3.09). Trascript score misZ 6.538 (greater than threshold 3.09). GenCC has associacion of gene with intellectual disability, autosomal dominant 57.
• BP4: Computational evidence support a benign effect (MetaRNN=0.3736871).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TLK2	NM_006852.6	c.226A>C	p.Lys76Gln	missense_variant, splice_region_variant	5/22	ENST00000346027.10	NP_006843.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TLK2	ENST00000346027.10	c.226A>C	p.Lys76Gln	missense_variant, splice_region_variant	5/22	1	NM_006852.6	ENSP00000275780	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jan 24, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	25
DANN	Benign	0.94
DEOGEN2	Benign	0.032	T;.;T;.;.
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D
M_CAP	Benign	0.075	D
MetaRNN	Benign	0.37	T;T;T;T;T
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Benign	1.4	.;L;L;L;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-1.3	.;N;N;N;.
REVEL	Uncertain	0.45
Sift	Benign	0.13	.;T;T;D;.
Sift4G	Uncertain	0.0080	D;T;T;T;T
Polyphen		0.14, 0.86, 0.91	.;B;P;P;.
Vest4		0.53, 0.36, 0.32
MutPred		0.17		Loss of ubiquitination at K76 (P = 0.0019);Loss of ubiquitination at K76 (P = 0.0019);Loss of ubiquitination at K76 (P = 0.0019);Loss of ubiquitination at K76 (P = 0.0019);Loss of ubiquitination at K76 (P = 0.0019);
MVP		0.73
MPC		1.5
ClinPred		0.82	D
GERP RS		5.3
Varity_R		0.26
gMVP		0.47

Splicing

Name	Calibrated prediction	Score	Prediction
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-60600497;