Genetic Variant TYK2:p.Glu1163Gly (chr19-10350910-T-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_003331.5(TYK2):c.3488A>G(p.Glu1163Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00388 in 1,614,180 control chromosomes in the GnomAD database, including 94 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E1163K) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0032 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0039 ( 90 hom. )

Consequence

TYK2
NM_003331.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 1.65

Publications

22 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

new If you want to explore the variant's impact on the transcript NM_003331.5, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0062526166).

BP6

Variant 19-10350910-T-C is Benign according to our data. Variant chr19-10350910-T-C is described in ClinVar as Benign. ClinVar VariationId is 468764.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00322 (491/152300) while in subpopulation SAS AF = 0.0294 (142/4824). AF 95% confidence interval is 0.0255. There are 4 homozygotes in GnomAd4. There are 265 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

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.3488A>G	p.Glu1163Gly	missense	Exon 25 of 25	NP_003322.3
TYK2	NM_001385204.1		c.3698A>G	p.Glu1233Gly	missense	Exon 25 of 25	NP_001372133.1
TYK2	NM_001385203.1		c.3569A>G	p.Glu1190Gly	missense	Exon 26 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.3488A>G	p.Glu1163Gly	missense	Exon 25 of 25	ENSP00000431885.1	P29597
TYK2	ENST00000524462.5	TSL:1	c.2933A>G	p.Glu978Gly	missense	Exon 21 of 21	ENSP00000433203.1	E9PM19
TYK2	ENST00000531836.7	TSL:4	c.3488A>G	p.Glu1163Gly	missense	Exon 25 of 25	ENSP00000436175.2	P29597

Frequencies

GnomAD3 genomes

AF:

0.00322

AC:

490

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000507

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00360

Gnomad ASJ

AF:

0.00432

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0288

Gnomad FIN

AF:

0.00207

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.00319

Gnomad OTH

AF:

0.00526

GnomAD2 exomes

AF:

0.00596

AC:

1498

AN:

251488

AF XY:

0.00757

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.00121

Gnomad ASJ exome

AF:

0.00397

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00176

Gnomad NFE exome

AF:

0.00360

Gnomad OTH exome

AF:

0.00603

GnomAD4 exome

AF:

0.00395

AC:

5773

AN:

1461880

Hom.:

Cov.:

AF XY:

0.00490

AC XY:

3563

AN XY:

727240

show subpopulations

African (AFR)

AF:

0.000358

AC:

AN:

33480

American (AMR)

AF:

0.00157

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00386

AC:

101

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.0306

AC:

2640

AN:

86256

European-Finnish (FIN)

AF:

0.00185

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.0248

AC:

143

AN:

5762

European-Non Finnish (NFE)

AF:

0.00215

AC:

2395

AN:

1112012

Other (OTH)

AF:

0.00517

AC:

312

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

410

821

1231

1642

2052

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

188

282

376

470

<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:

0.00322

AC:

491

AN:

152300

Hom.:

Cov.:

AF XY:

0.00356

AC XY:

265

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.000505

AC:

AN:

41570

American (AMR)

AF:

0.00360

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00432

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5188

South Asian (SAS)

AF:

0.0294

AC:

142

AN:

4824

European-Finnish (FIN)

AF:

0.00207

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00319

AC:

217

AN:

68028

Other (OTH)

AF:

0.00473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

112

140

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00380

Hom.:

Bravo

AF:

0.00255

Asia WGS

AF:

0.00866

AC:

AN:

3478

EpiCase

AF:

0.00502

EpiControl

AF:

0.00462

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Immunodeficiency 35 (2)

not specified (2)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.26

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.36

Eigen

Benign

0.042

Eigen_PC

Benign

0.13

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.20

MetaRNN

Benign

0.0063

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.65

PhyloP100

1.6

PrimateAI

Benign

0.31

PROVEAN

Benign

-1.9

REVEL

Benign

0.22

Sift

Uncertain

0.020

Sift4G

Benign

0.21

Varity_R

0.28

gMVP

0.28

Mutation Taster

=66/34

polymorphism

(source)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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