19-49746539-C-A

Variant names:

• chr19-49746539-C-A
• NM_021733.2:c.923G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_021733.2(TSKS):​c.923G>T​(p.Arg308Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TSKS NM_021733.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.820
• Publications: 0 publications found

Genes affected

TSKS (HGNC:30719): (testis specific serine kinase substrate) This gene may play a role in testicular physiology, spermatogenesis or spermiogenesis. Expression of the encoded protein is highest in the testis and down-regulated in testicular cancer. The gene is localized to the region 19q13.3 among the related RAS viral oncogene homolog (RRAS) and interferon regulatory factor 3 (IRF3) genes, which are both involved in tumorigenesis pathways and progression. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.362728).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021733.2. 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
	TSKS	NM_021733.2	MANE Select	c.923G>T	p.Arg308Leu	missense	Exon 6 of 11	NP_068379.1	Q9UJT2-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSKS	ENST00000246801.8	TSL:1 MANE Select	c.923G>T	p.Arg308Leu	missense	Exon 6 of 11	ENSP00000246801.2	Q9UJT2-1
	TSKS	ENST00000358830.3	TSL:1	c.323G>T	p.Arg108Leu	missense	Exon 2 of 7	ENSP00000351691.2	C9K0I0

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.088	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.010	T
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.079	N
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.36	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L
PhyloP100		0.82
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.15
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.0090	D
Polyphen		0.30	B
Vest4		0.62
MutPred		0.31		Loss of disorder (P = 0.1503)
MVP		0.082
MPC		0.71
ClinPred		0.80	D
GERP RS		2.7
Varity_R		0.10
gMVP		0.18
Mutation Taster		=96/4	polymorphism

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

hg19: chr19-50249796; COSMIC: COSV99883175;