rs55882956

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_003331.5(TYK2):c.2107C>T(p.Arg703Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00298 in 1,610,784 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0028 ( 4 hom., cov: 31)

Exomes 𝑓: 0.0030 ( 36 hom. )

Consequence

TYK2
NM_003331.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 1.13

Variant links:

Genes affected

TYK2 (HGNC:12440): (tyrosine kinase 2) This gene encodes a member of the tyrosine kinase and, more specifically, the Janus kinases (JAKs) protein families. This protein associates with the cytoplasmic domain of type I and type II cytokine receptors and promulgate cytokine signals by phosphorylating receptor subunits. It is also a component of both the type I and type III interferon signaling pathways. As such, it may play a role in anti-viral immunity. A mutation in this gene has been associated with Immunodeficiency 35. [provided by RefSeq, Sep 2020]

TYK2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006138116).

BP6

Variant 19-10359243-G-A is Benign according to our data. Variant chr19-10359243-G-A is described in ClinVar as [Benign]. Clinvar id is 327942.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-10359243-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00283 (431/152282) while in subpopulation EAS AF= 0.0261 (135/5172). AF 95% confidence interval is 0.0225. There are 4 homozygotes in gnomad4. There are 210 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TYK2	NM_003331.5 linkuse as main transcript	c.2107C>T	p.Arg703Trp	missense_variant	15/25	ENST00000525621.6	NP_003322.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TYK2	ENST00000525621.6 linkuse as main transcript	c.2107C>T	p.Arg703Trp	missense_variant	15/25	1	NM_003331.5	ENSP00000431885	P1

Frequencies

GnomAD3 genomes

AF:

0.00286

AC:

435

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000603

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0100

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.0264

Gnomad SAS

AF:

0.00373

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00135

Gnomad OTH

AF:

0.00383

GnomAD3 exomes

AF:

0.00721

AC:

1779

AN:

246894

Hom.:

AF XY:

0.00609

AC XY:

817

AN XY:

134206

show subpopulations

Gnomad AFR exome

AF:

0.000502

Gnomad AMR exome

AF:

0.0283

Gnomad ASJ exome

AF:

0.000801

Gnomad EAS exome

AF:

0.0301

Gnomad SAS exome

AF:

0.00259

Gnomad FIN exome

AF:

0.0000507

Gnomad NFE exome

AF:

0.00116

Gnomad OTH exome

AF:

0.00495

GnomAD4 exome

AF:

0.00300

AC:

4372

AN:

1458502

Hom.:

Cov.:

AF XY:

0.00291

AC XY:

2112

AN XY:

725646

show subpopulations

Gnomad4 AFR exome

AF:

0.000329

Gnomad4 AMR exome

AF:

0.0254

Gnomad4 ASJ exome

AF:

0.000727

Gnomad4 EAS exome

AF:

0.0270

Gnomad4 SAS exome

AF:

0.00269

Gnomad4 FIN exome

AF:

0.0000991

Gnomad4 NFE exome

AF:

0.00154

Gnomad4 OTH exome

AF:

0.00305

GnomAD4 genome

AF:

0.00283

AC:

431

AN:

152282

Hom.:

Cov.:

AF XY:

0.00282

AC XY:

210

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.000601

Gnomad4 AMR

AF:

0.00994

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.0261

Gnomad4 SAS

AF:

0.00353

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00135

Gnomad4 OTH

AF:

0.00379

Alfa

AF:

0.00167

Hom.:

Bravo

AF:

0.00446

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00174

AC:

ExAC

AF:

0.00664

AC:

806

Asia WGS

AF:

0.0120

AC:

AN:

3478

EpiCase

AF:

0.000927

EpiControl

AF:

0.00119

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 31118190, 28842327) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Immunodeficiency 35

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.21

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.63

D;D;D;.

Eigen

Benign

-0.18

Eigen_PC

Benign

-0.37

FATHMM_MKL

Benign

0.44

LIST_S2

Uncertain

0.93

D;D;.;D

MetaRNN

Benign

0.0061

T;T;T;T

MetaSVM

Benign

-0.45

MutationAssessor

Pathogenic

2.9

M;.;M;.

MutationTaster

Benign

0.96

D;D;D;D

PrimateAI

Benign

0.43

PROVEAN

Uncertain

-4.0

D;D;D;D

REVEL

Benign

0.21

Sift

Uncertain

0.0010

D;D;D;D

Sift4G

Uncertain

0.0030

D;D;D;D

Polyphen

1.0

D;.;D;D

Vest4

0.44

MVP

0.53

MPC

0.90

ClinPred

0.036

GERP RS

0.034

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.6

Varity_R

0.32

gMVP

0.57

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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