22-19132208-C-T

Position:

chr22-19132208-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_053006.5(TSSK2):c.809C>T(p.Ser270Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000429 in 1,612,438 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00030 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00044 ( 0 hom. )

Consequence

TSSK2
NM_053006.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.17

Variant links:

Genes affected

TSSK2 (HGNC:11401): (testis specific serine kinase 2) TSSK2 belongs to a family of serine/threonine kinases highly expressed in testis (Hao et al., 2004 [PubMed 15044604]).[supplied by OMIM, Mar 2008]

TSSK2 links:

ESS2 (HGNC:16817): (ess-2 splicing factor homolog) This gene is located within the minimal DGS critical region (MDGCR) thought to contain the gene(s) responsible for a group of developmental disorders. These disorders include DiGeorge syndrome, velocardiofacial syndrome, conotruncal anomaly face syndrome, and some familial or sporadic conotruncal cardiac defects which have been associated with microdeletion of 22q11.2. The encoded protein may be a component of C complex spliceosomes, and the orthologous protein in the mouse localizes to the nucleus. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Dec 2015]

ESS2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.08154577).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSSK2	NM_053006.5 linkuse as main transcript	c.809C>T	p.Ser270Leu	missense_variant	1/1	ENST00000399635.4	NP_443732.3
ESS2	NM_022719.3 linkuse as main transcript	c.*1988G>A		3_prime_UTR_variant	10/10	ENST00000252137.11	NP_073210.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSSK2	ENST00000399635.4 linkuse as main transcript	c.809C>T	p.Ser270Leu	missense_variant	1/1		NM_053006.5	ENSP00000382544	P1
ESS2	ENST00000252137.11 linkuse as main transcript	c.*1988G>A		3_prime_UTR_variant	10/10	1	NM_022719.3	ENSP00000252137	P1

Frequencies

GnomAD3 genomes

AF:

0.000302

AC:

AN:

152098

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000368

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000244

AC:

AN:

250040

Hom.:

AF XY:

0.000244

AC XY:

AN XY:

135332

show subpopulations

Gnomad AFR exome

AF:

0.000494

Gnomad AMR exome

AF:

0.000260

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000373

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.000442

AC:

645

AN:

1460222

Hom.:

Cov.:

AF XY:

0.000413

AC XY:

300

AN XY:

726066

show subpopulations

Gnomad4 AFR exome

AF:

0.000299

Gnomad4 AMR exome

AF:

0.000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.000552

Gnomad4 OTH exome

AF:

0.000166

GnomAD4 genome

AF:

0.000302

AC:

AN:

152216

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

AN XY:

74416

show subpopulations

Gnomad4 AFR

AF:

0.000481

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000368

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000356

Hom.:

Bravo

AF:

0.000363

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000222

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000830

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 09, 2022

The c.809C>T (p.S270L) alteration is located in exon 1 (coding exon 1) of the TSSK2 gene. This alteration results from a C to T substitution at nucleotide position 809, causing the serine (S) at amino acid position 270 to be replaced by a leucine (L). 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

0.083

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.30

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.11

Eigen

Benign

-0.52

Eigen_PC

Benign

-0.44

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.21

M_CAP

Benign

0.042

MetaRNN

Benign

0.082

MetaSVM

Benign

-0.71

MutationAssessor

Benign

1.7

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.32

PROVEAN

Benign

-1.9

REVEL

Benign

0.20

Sift

Benign

0.30

Sift4G

Benign

0.33

Polyphen

0.0020

Vest4

0.25

MVP

0.79

MPC

0.31

ClinPred

0.0080

GERP RS

3.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.071

gMVP

0.26

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over