19-10359299-A-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PP3_ModerateBP6_Very_StrongBA1

The NM_003331.5(TYK2):c.2051T>G(p.Ile684Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0797 in 1,610,644 control chromosomes in the GnomAD database, including 5,961 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. I684I) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.057 ( 346 hom., cov: 32)

Exomes 𝑓: 0.082 ( 5615 hom. )

Consequence

TYK2
NM_003331.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 7.08

Publications

191 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: Labcorp Genetics (formerly Invitae), Orphanet

TYK2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

BP6

Variant 19-10359299-A-C is Benign according to our data. Variant chr19-10359299-A-C is described in ClinVar as Benign. ClinVar VariationId is 259043.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.084 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003331.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TYK2	NM_003331.5	MANE Select	c.2051T>G	p.Ile684Ser	missense	Exon 15 of 25	NP_003322.3
TYK2	NM_001385204.1		c.2051T>G	p.Ile684Ser	missense	Exon 15 of 25	NP_001372133.1
TYK2	NM_001385203.1		c.2051T>G	p.Ile684Ser	missense	Exon 15 of 26	NP_001372132.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TYK2	ENST00000525621.6	TSL:1 MANE Select	c.2051T>G	p.Ile684Ser	missense	Exon 15 of 25	ENSP00000431885.1	P29597
TYK2	ENST00000524462.5	TSL:1	c.1496T>G	p.Ile499Ser	missense	Exon 11 of 21	ENSP00000433203.1	E9PM19
TYK2	ENST00000531836.7	TSL:4	c.2051T>G	p.Ile684Ser	missense	Exon 15 of 25	ENSP00000436175.2	P29597

Frequencies

GnomAD3 genomes

AF:

0.0574

AC:

8727

AN:

152112

Hom.:

346

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0153

Gnomad AMI

AF:

0.0504

Gnomad AMR

AF:

0.0533

Gnomad ASJ

AF:

0.0963

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00912

Gnomad FIN

AF:

0.0823

Gnomad MID

AF:

0.0791

Gnomad NFE

AF:

0.0859

Gnomad OTH

AF:

0.0574

GnomAD2 exomes

AF:

0.0608

AC:

15034

AN:

247106

AF XY:

0.0605

show subpopulations

Gnomad AFR exome

AF:

0.0146

Gnomad AMR exome

AF:

0.0356

Gnomad ASJ exome

AF:

0.103

Gnomad EAS exome

AF:

0.000164

Gnomad FIN exome

AF:

0.0826

Gnomad NFE exome

AF:

0.0908

Gnomad OTH exome

AF:

0.0770

GnomAD4 exome

AF:

0.0820

AC:

119592

AN:

1458414

Hom.:

5615

Cov.:

AF XY:

0.0800

AC XY:

58075

AN XY:

725602

show subpopulations

African (AFR)

AF:

0.0128

AC:

427

AN:

33480

American (AMR)

AF:

0.0390

AC:

1740

AN:

44628

Ashkenazi Jewish (ASJ)

AF:

0.100

AC:

2623

AN:

26112

East Asian (EAS)

AF:

0.000176

AC:

AN:

39676

South Asian (SAS)

AF:

0.00993

AC:

856

AN:

86174

European-Finnish (FIN)

AF:

0.0835

AC:

4218

AN:

50506

Middle Eastern (MID)

AF:

0.0573

AC:

330

AN:

5764

European-Non Finnish (NFE)

AF:

0.0942

AC:

104722

AN:

1111722

Other (OTH)

AF:

0.0774

AC:

4669

AN:

60352

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

6003

12006

18009

24012

30015

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3718

7436

11154

14872

18590

<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:

0.0573

AC:

8721

AN:

152230

Hom.:

346

Cov.:

AF XY:

0.0553

AC XY:

4118

AN XY:

74418

show subpopulations

African (AFR)

AF:

0.0152

AC:

633

AN:

41562

American (AMR)

AF:

0.0533

AC:

814

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.0963

AC:

334

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00913

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.0823

AC:

871

AN:

10588

Middle Eastern (MID)

AF:

0.0748

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0858

AC:

5837

AN:

68006

Other (OTH)

AF:

0.0568

AC:

120

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

440

879

1319

1758

2198

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

200

300

400

500

<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:

0.0750

Hom.:

2259

Bravo

AF:

0.0555

TwinsUK

AF:

0.0987

AC:

366

ALSPAC

AF:

0.0952

AC:

367

ESP6500AA

AF:

0.0200

AC:

ESP6500EA

AF:

0.0944

AC:

812

ExAC

AF:

0.0605

AC:

7346

Asia WGS

AF:

0.00693

AC:

AN:

3478

EpiCase

AF:

0.0846

EpiControl

AF:

0.0863

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Immunodeficiency 35 (2)

not provided (2)

not specified (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.59

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Uncertain

-0.040

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.47

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

MetaRNN

Benign

0.0056

MetaSVM

Benign

-0.73

MutationAssessor

Uncertain

2.4

PhyloP100

7.1

PrimateAI

Uncertain

0.61

PROVEAN

Pathogenic

-5.1

REVEL

Uncertain

0.34

Sift

Uncertain

0.0070

Sift4G

Uncertain

0.0060

Polyphen

1.0

Vest4

0.33

MPC

1.1

ClinPred

0.035

GERP RS

3.7

Varity_R

0.74

gMVP

0.90

Mutation Taster

=69/31

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.86

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.86

Position offset: -1

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over