17-62481156-C-T

Variant names:

• chr17-62481156-C-T
• rs2144333874
• ENST00000582809.5:c.-563C>T

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_001330418.3(TLK2):​c.-467C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TLK2 NM_001330418.3 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 2.48
• Publications: 0 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: BayesDel_addAF computational evidence supports a deleterious effect, 0.522
• PP5: Variant 17-62481156-C-T is Pathogenic according to our data. Variant chr17-62481156-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1320192.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001330418.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TLK2	NM_006852.6	MANE Select	c.31C>T	p.Arg11*	stop_gained	Exon 2 of 22	NP_006843.2
	TLK2	NM_001330418.3		c.-467C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 22	NP_001317347.1	J3QLK5
	TLK2	NM_001375273.1		c.-467C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 22	NP_001362202.1	J3QLK5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TLK2	ENST00000582809.5	TSL:1	c.-563C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 23	ENSP00000463595.1	J3QLK5
	TLK2	ENST00000346027.10	TSL:1 MANE Select	c.31C>T	p.Arg11*	stop_gained	Exon 2 of 22	ENSP00000275780.7	Q86UE8-2
	TLK2	ENST00000326270.13	TSL:1	c.31C>T	p.Arg11*	stop_gained	Exon 2 of 23	ENSP00000316512.9	Q86UE8-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Intellectual disability, autosomal dominant 57 (2)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	37
DANN	Uncertain	1.0
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.77	D
PhyloP100		2.5
Vest4		0.41
GERP RS		2.7
PromoterAI		-0.010	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Other links and lift over

dbSNP: rs2144333874; hg19: chr17-60558517; COSMIC: COSV58298844;