NM_003331.5:c.1084G>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 14/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. V362V) has been classified as Likely 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

Publications

222 publications found

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 Gene-Disease associations (from GenCC):

immunodeficiency 35
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

TYK2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 259040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
TYK2	NM_003331.5 link	c.1084G>T	p.Val362Phe	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.1084G>T	p.Val362Phe	missense_variant	Exon 8 of 25	1	NM_003331.5	ENSP00000431885.1		P29597

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

GnomAD2 exomes

AF:

0.275

AC:

68753

AN:

250350

AF XY:

0.277

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 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

African (AFR)

AF:

0.103

AC:

3435

AN:

33478

American (AMR)

AF:

0.204

AC:

9099

AN:

44692

Ashkenazi Jewish (ASJ)

AF:

0.306

AC:

8001

AN:

26132

East Asian (EAS)

AF:

0.445

AC:

17659

AN:

39670

South Asian (SAS)

AF:

0.263

AC:

22725

AN:

86244

European-Finnish (FIN)

AF:

0.248

AC:

13197

AN:

53166

Middle Eastern (MID)

AF:

0.283

AC:

1633

AN:

5766

European-Non Finnish (NFE)

AF:

0.285

AC:

317302

AN:

1111866

Other (OTH)

AF:

0.290

AC:

17494

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

18993

37987

56980

75974

94967

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10582

21164

31746

42328

52910

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.233

AC:

35457

AN:

152316

Hom.:

4829

Cov.:

AF XY:

0.232

AC XY:

17243

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.110

AC:

4563

AN:

41584

American (AMR)

AF:

0.226

AC:

3465

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.323

AC:

1118

AN:

3466

East Asian (EAS)

AF:

0.511

AC:

2650

AN:

5184

South Asian (SAS)

AF:

0.273

AC:

1320

AN:

4832

European-Finnish (FIN)

AF:

0.234

AC:

2482

AN:

10618

Middle Eastern (MID)

AF:

0.279

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.278

AC:

18889

AN:

68016

Other (OTH)

AF:

0.243

AC:

513

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1379

2758

4137

5516

6895

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

388

776

1164

1552

1940

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.270

Hom.:

27738

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

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 -

Nov 12, 2023

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 26338038, 31961910, 19567624, 28973304, 26502338, 15657875) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Immunodeficiency 35

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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. -

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

(source)

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;.

PhyloP100

0.13

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

Mutation Taster

=94/6

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over