rs2304255

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_003331.5(TYK2):c.1087G>A(p.Gly363Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0703 in 1,613,992 control chromosomes in the GnomAD database, including 4,365 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.055 ( 295 hom., cov: 33)

Exomes 𝑓: 0.072 ( 4070 hom. )

Consequence

TYK2
NM_003331.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -1.30

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=0.002353698).

BP6

Variant 19-10364973-C-T is Benign according to our data. Variant chr19-10364973-C-T is described in ClinVar as [Benign]. Clinvar id is 137864.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0765 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TYK2	NM_003331.5 link	c.1087G>A	p.Gly363Ser	missense_variant	Exon 8 of 25	ENST00000525621.6	NP_003322.3	P29597A0A024R7E4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TYK2	ENST00000525621.6 link	c.1087G>A	p.Gly363Ser	missense_variant	Exon 8 of 25	1	NM_003331.5	ENSP00000431885.1		P29597

Frequencies

GnomAD3 genomes

AF:

0.0550

AC:

8378

AN:

152256

Hom.:

291

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0157

Gnomad AMI

AF:

0.0789

Gnomad AMR

AF:

0.0463

Gnomad ASJ

AF:

0.0724

Gnomad EAS

AF:

0.0250

Gnomad SAS

AF:

0.0775

Gnomad FIN

AF:

0.0688

Gnomad MID

AF:

0.0764

Gnomad NFE

AF:

0.0782

Gnomad OTH

AF:

0.0550

GnomAD3 exomes

AF:

0.0622

AC:

15602

AN:

250708

Hom.:

593

AF XY:

0.0647

AC XY:

8781

AN XY:

135672

show subpopulations

Gnomad AFR exome

AF:

0.0154

Gnomad AMR exome

AF:

0.0312

Gnomad ASJ exome

AF:

0.0729

Gnomad EAS exome

AF:

0.0239

Gnomad SAS exome

AF:

0.0827

Gnomad FIN exome

AF:

0.0670

Gnomad NFE exome

AF:

0.0768

Gnomad OTH exome

AF:

0.0711

GnomAD4 exome

AF:

0.0719

AC:

105111

AN:

1461618

Hom.:

4070

Cov.:

AF XY:

0.0727

AC XY:

52865

AN XY:

727128

show subpopulations

Gnomad4 AFR exome

AF:

0.0146

Gnomad4 AMR exome

AF:

0.0334

Gnomad4 ASJ exome

AF:

0.0699

Gnomad4 EAS exome

AF:

0.0156

Gnomad4 SAS exome

AF:

0.0813

Gnomad4 FIN exome

AF:

0.0671

Gnomad4 NFE exome

AF:

0.0769

Gnomad4 OTH exome

AF:

0.0692

GnomAD4 genome

AF:

0.0551

AC:

8399

AN:

152374

Hom.:

295

Cov.:

AF XY:

0.0547

AC XY:

4079

AN XY:

74514

show subpopulations

Gnomad4 AFR

AF:

0.0159

Gnomad4 AMR

AF:

0.0463

Gnomad4 ASJ

AF:

0.0724

Gnomad4 EAS

AF:

0.0248

Gnomad4 SAS

AF:

0.0774

Gnomad4 FIN

AF:

0.0688

Gnomad4 NFE

AF:

0.0782

Gnomad4 OTH

AF:

0.0596

Alfa

AF:

0.0662

Hom.:

174

Bravo

AF:

0.0516

TwinsUK

AF:

0.0782

AC:

290

ALSPAC

AF:

0.0789

AC:

304

ESP6500AA

AF:

0.0175

AC:

ESP6500EA

AF:

0.0784

AC:

674

ExAC

AF:

0.0636

AC:

7724

Asia WGS

AF:

0.0610

AC:

213

AN:

3478

EpiCase

AF:

0.0771

EpiControl

AF:

0.0738

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Immunodeficiency 35

Benign:3

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

May 18, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:2

Mar 06, 2014

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.75

CADD

Benign

0.029

DANN

Benign

0.58

DEOGEN2

Benign

0.051

T;T;T;.

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.036

LIST_S2

Benign

0.21

T;T;.;T

MetaRNN

Benign

0.0024

T;T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.67

N;.;N;.

PrimateAI

Benign

0.22

PROVEAN

Benign

0.53

N;N;N;N

REVEL

Benign

0.027

Sift

Benign

0.48

T;T;T;T

Sift4G

Benign

0.71

T;T;T;T

Polyphen

0.0020

B;.;B;B

Vest4

0.047

MPC

0.26

ClinPred

0.0015

GERP RS

-6.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.040

gMVP

0.13

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