rs2304256

Positions:

chr19-10364976-C-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_003331.5(TYK2):c.1084G>T(p.Val362Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.276 in 1,613,710 control chromosomes in the GnomAD database, including 64,683 homozygotes. 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 Benign (★★).

Frequency

Genomes: 𝑓 0.23 ( 4829 hom., cov: 34)

Exomes 𝑓: 0.28 ( 59854 hom. )

Consequence

TYK2
NM_003331.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.133

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 -16 ACMG points.

BP6

Variant 19-10364976-C-A is Benign according to our data. Variant chr19-10364976-C-A is described in ClinVar as [Benign]. Clinvar id is 259040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-10364976-C-A is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.495 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TYK2	NM_003331.5 linkuse as main transcript	c.1084G>T	p.Val362Phe	missense_variant	8/25	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.1084G>T	p.Val362Phe	missense_variant	8/25	1	NM_003331.5	ENSP00000431885	P1

Frequencies

GnomAD3 genomes

AF:

0.233

AC:

35442

AN:

152198

Hom.:

4824

Cov.:

show subpopulations

Gnomad AFR

AF:

0.110

Gnomad AMI

AF:

0.415

Gnomad AMR

AF:

0.226

Gnomad ASJ

AF:

0.323

Gnomad EAS

AF:

0.511

Gnomad SAS

AF:

0.274

Gnomad FIN

AF:

0.234

Gnomad MID

AF:

0.272

Gnomad NFE

AF:

0.278

Gnomad OTH

AF:

0.244

GnomAD3 exomes

AF:

0.275

AC:

68753

AN:

250350

Hom.:

10480

AF XY:

0.277

AC XY:

37519

AN XY:

135450

show subpopulations

Gnomad AFR exome

AF:

0.110

Gnomad AMR exome

AF:

0.199

Gnomad ASJ exome

AF:

0.306

Gnomad EAS exome

AF:

0.535

Gnomad SAS exome

AF:

0.266

Gnomad FIN exome

AF:

0.240

Gnomad NFE exome

AF:

0.285

Gnomad OTH exome

AF:

0.279

GnomAD4 exome

AF:

0.281

AC:

410545

AN:

1461394

Hom.:

59854

Cov.:

AF XY:

0.281

AC XY:

204019

AN XY:

727000

show subpopulations

Gnomad4 AFR exome

AF:

0.103

Gnomad4 AMR exome

AF:

0.204

Gnomad4 ASJ exome

AF:

0.306

Gnomad4 EAS exome

AF:

0.445

Gnomad4 SAS exome

AF:

0.263

Gnomad4 FIN exome

AF:

0.248

Gnomad4 NFE exome

AF:

0.285

Gnomad4 OTH exome

AF:

0.290

GnomAD4 genome

AF:

0.233

AC:

35457

AN:

152316

Hom.:

4829

Cov.:

AF XY:

0.232

AC XY:

17243

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.110

Gnomad4 AMR

AF:

0.226

Gnomad4 ASJ

AF:

0.323

Gnomad4 EAS

AF:

0.511

Gnomad4 SAS

AF:

0.273

Gnomad4 FIN

AF:

0.234

Gnomad4 NFE

AF:

0.278

Gnomad4 OTH

AF:

0.243

Alfa

AF:

0.276

Hom.:

13701

Bravo

AF:

0.231

TwinsUK

AF:

0.293

AC:

1086

ALSPAC

AF:

0.291

AC:

1122

ESP6500AA

AF:

0.116

AC:

510

ESP6500EA

AF:

0.280

AC:

2411

ExAC

AF:

0.275

AC:

33403

Asia WGS

AF:

0.347

AC:

1203

AN:

3478

EpiCase

AF:

0.283

EpiControl

AF:

0.276

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Nov 12, 2023	This variant is classified as Benign based on local population frequency. This variant was detected in 42% of patients studied by a panel of primary immunodeficiencies. Number of patients: 40. Only high quality variants are reported. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 26338038, 31961910, 19567624, 28973304, 26502338, 15657875) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Immunodeficiency 35

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.65

CADD

Benign

7.3

DANN

Benign

0.84

DEOGEN2

Benign

0.067

T;T;T;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.31

LIST_S2

Benign

0.52

T;T;.;T

MetaRNN

Benign

0.00015

T;T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

1.0

L;.;L;.

MutationTaster

Benign

1.0

P;P;P;P

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.52

N;N;N;N

REVEL

Benign

0.053

Sift

Benign

0.092

T;T;T;T

Sift4G

Uncertain

0.056

T;T;T;T

Polyphen

0.015

B;.;B;B

Vest4

0.077

MPC

0.37

ClinPred

0.0021

GERP RS

-0.83

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.056

gMVP

0.27

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.27

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.27

Position offset: -9

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