1-45345878-C-G

Variant names:

• chr1-45345878-C-G
• rs778883567
• NM_007170.3:c.996G>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_007170.3(TESK2):​c.996G>C​(p.Arg332Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,076 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 18/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R332T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: TESK2 NM_007170.3 missense, splice_region
• Scores: Splicing: ADA: 0.0002672
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0330

Genes affected

TESK2 (HGNC:11732): (testis associated actin remodelling kinase 2) This gene product is a serine/threonine protein kinase that contains an N-terminal protein kinase domain that is structurally similar to the kinase domains of testis-specific protein kinase-1 and the LIM motif-containing protein kinases (LIMKs). Its overall structure is most related to the former, indicating that it belongs to the TESK subgroup of the LIMK/TESK family of protein kinases. This gene is predominantly expressed in testis and prostate. The developmental expression pattern of the rat gene in testis suggests an important role for this gene in meitoic stages and/or early stages of spermiogenesis. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2016]

ENSG00000288208 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08557603).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TESK2	NM_007170.3	c.996G>C	p.Arg332Ser	missense_variant, splice_region_variant	Exon 10 of 11	ENST00000372086.4	NP_009101.2
TESK2	NM_001320800.2	c.747G>C	p.Arg249Ser	missense_variant, splice_region_variant	Exon 9 of 10		NP_001307729.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TESK2	ENST00000372086.4	c.996G>C	p.Arg332Ser	missense_variant, splice_region_variant	Exon 10 of 11	1	NM_007170.3	ENSP00000361158.3
TESK2	ENST00000372084.5	c.909G>C	p.Arg303Ser	missense_variant, splice_region_variant	Exon 8 of 9	1		ENSP00000361156.1
ENSG00000288208	ENST00000671898.1	n.540+9425G>C		intron_variant	Intron 5 of 20			ENSP00000499896.1
TESK2	ENST00000486676.5	n.1343G>C		splice_region_variant, non_coding_transcript_exon_variant	Exon 9 of 10	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 249470 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135336

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461076 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 726900

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 28, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.996G>C (p.R332S) alteration is located in exon 10 (coding exon 9) of the TESK2 gene. This alteration results from a G to C substitution at nucleotide position 996, causing the arginine (R) at amino acid position 332 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	7.7
DANN	Benign	0.96
DEOGEN2	Benign	0.0083	.;T
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.63	T;T
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.086	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.69	.;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.060	N;N
REVEL	Benign	0.045
Sift	Benign	0.098	T;T
Sift4G	Benign	0.45	T;T
Polyphen		0.0	B;B
Vest4		0.16
MutPred		0.29		.;Loss of MoRF binding (P = 0.0103);
MVP		0.60
MPC		0.22
ClinPred		0.074	T
GERP RS		0.57
Varity_R		0.088
gMVP		0.36

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00027
dbscSNV1_RF	Benign	0.026
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: rs778883567; hg19: chr1-45811550;