NM_006852.6:c.164A>G

Variant names:

• chr17-62522214-A-G
• NM_006852.6:c.164A>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_006852.6(TLK2):​c.164A>G​(p.Lys55Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TLK2 NM_006852.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.43

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the TLK2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 18 curated pathogenic missense variants (we use a threshold of 10). The gene has 4 curated benign missense variants. Gene score misZ: 4.4909 (above the threshold of 3.09). Trascript score misZ: 6.538 (above the threshold of 3.09). GenCC associations: The gene is linked to intellectual disability, autosomal dominant 57.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TLK2	NM_006852.6	c.164A>G	p.Lys55Arg	missense_variant	Exon 4 of 22	ENST00000346027.10	NP_006843.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TLK2	ENST00000346027.10	c.164A>G	p.Lys55Arg	missense_variant	Exon 4 of 22	1	NM_006852.6	ENSP00000275780.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Nov 28, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	0.12
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Pathogenic	26
DANN	Benign	0.97
DEOGEN2	Benign	0.13	.;T;.;T;.;.
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;D;D;D;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.52	D;D;D;D;D;D
MetaSVM	Uncertain	0.45	D
MutationAssessor	Uncertain	2.1	.;.;M;M;M;.
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.5	.;.;N;N;N;.
REVEL	Uncertain	0.43
Sift	Benign	0.11	.;.;T;T;D;.
Sift4G	Pathogenic	0.0	D;D;T;T;T;T
Polyphen		1.0, 1.0, 1.0	.;.;D;D;D;.
Vest4		0.53, 0.39, 0.39
MutPred		0.23		Loss of methylation at K55 (P = 0.0013);Loss of methylation at K55 (P = 0.0013);Loss of methylation at K55 (P = 0.0013);Loss of methylation at K55 (P = 0.0013);Loss of methylation at K55 (P = 0.0013);Loss of methylation at K55 (P = 0.0013);
MVP		0.87
MPC		1.4
ClinPred		0.90	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.25
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: chr17-60599575;