17-62481192-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 3P and 12B. PM2 PP2 BP4_Moderate BP6_Moderate BS1 BS2

The NM_006852.6(TLK2):c.67G>A(p.Val23Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,461,584 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: TLK2 NM_006852.6 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 6.93

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 -9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, TLK2
• BP4: Computational evidence support a benign effect (MetaRNN=0.21947429).
• BP6: Variant 17-62481192-G-A is Benign according to our data. Variant chr17-62481192-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3177847.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.00000342 (5/1461584) while in subpopulation EAS AF= 0.000101 (4/39682). AF 95% confidence interval is 0.0000335. There are 0 homozygotes in gnomad4_exome. There are 1 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High AC in GnomAdExome at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TLK2	NM_006852.6	c.67G>A	p.Val23Ile	missense_variant	2/22	ENST00000346027.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TLK2	ENST00000346027.10	c.67G>A	p.Val23Ile	missense_variant	2/22	1	NM_006852.6	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 251142 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135726

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000272

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461584 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727096

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 19, 2024

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.27
Cadd	Uncertain	24
Dann	Benign	0.95
Eigen	Benign	0.082
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.88	D;D;D;D;D;D;D
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.22	T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.24	T
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.68	T
Sift4G	Benign	0.087	T;T;T;T;T;T;T
Polyphen		0.063, 0.068, 0.15	.;.;.;B;B;B;.
Vest4		0.30, 0.29, 0.32
MutPred		0.19		Loss of helix (P = 0.0033);Loss of helix (P = 0.0033);Loss of helix (P = 0.0033);Loss of helix (P = 0.0033);Loss of helix (P = 0.0033);Loss of helix (P = 0.0033);Loss of helix (P = 0.0033);
MVP		0.62
MPC		1.2
ClinPred		0.24	T
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.099
gMVP		0.23

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

LitVar

Other links and lift over

dbSNP: rs760380556; hg19: chr17-60558553;