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.157G>A(p.Ala53Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00929 in 1,612,958 control chromosomes in the GnomAD database, including 95 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0072 ( 8 hom., cov: 32)

Exomes 𝑓: 0.0095 ( 87 hom. )

Consequence

TYK2
NM_003331.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 4.50

Publications

34 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0094073415).

BP6

Variant 19-10378250-C-T is Benign according to our data. Variant chr19-10378250-C-T is described in ClinVar as Benign. ClinVar VariationId is 378838.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00723 (1100/152232) while in subpopulation NFE AF = 0.0116 (786/67988). AF 95% confidence interval is 0.0109. There are 8 homozygotes in GnomAd4. There are 534 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 8 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.157G>A	p.Ala53Thr	missense	Exon 3 of 25	NP_003322.3
TYK2	NM_001385204.1		c.157G>A	p.Ala53Thr	missense	Exon 3 of 25	NP_001372133.1
TYK2	NM_001385203.1		c.157G>A	p.Ala53Thr	missense	Exon 3 of 26	NP_001372132.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TYK2	ENST00000525621.6	TSL:1 MANE Select	c.157G>A	p.Ala53Thr	missense	Exon 3 of 25	ENSP00000431885.1
TYK2	ENST00000524462.5	TSL:1	c.-91+2260G>A		intron	N/A	ENSP00000433203.1
TYK2	ENST00000531836.7	TSL:4	c.157G>A	p.Ala53Thr	missense	Exon 3 of 25	ENSP00000436175.2

Frequencies

GnomAD3 genomes

AF:

0.00723

AC:

1100

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00176

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00629

Gnomad ASJ

AF:

0.00576

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00806

Gnomad FIN

AF:

0.00517

Gnomad MID

AF:

0.0411

Gnomad NFE

AF:

0.0116

Gnomad OTH

AF:

0.00813

GnomAD2 exomes

AF:

0.00735

AC:

1839

AN:

250170

AF XY:

0.00785

show subpopulations

Gnomad AFR exome

AF:

0.00198

Gnomad AMR exome

AF:

0.00370

Gnomad ASJ exome

AF:

0.00529

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00434

Gnomad NFE exome

AF:

0.0109

Gnomad OTH exome

AF:

0.00835

GnomAD4 exome

AF:

0.00950

AC:

13880

AN:

1460726

Hom.:

Cov.:

AF XY:

0.00952

AC XY:

6920

AN XY:

726654

show subpopulations

African (AFR)

AF:

0.00122

AC:

AN:

33478

American (AMR)

AF:

0.00369

AC:

165

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00517

AC:

135

AN:

26128

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39698

South Asian (SAS)

AF:

0.00865

AC:

746

AN:

86258

European-Finnish (FIN)

AF:

0.00537

AC:

281

AN:

52324

Middle Eastern (MID)

AF:

0.0106

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0108

AC:

11996

AN:

1111976

Other (OTH)

AF:

0.00752

AC:

454

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

815

1630

2445

3260

4075

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

438

876

1314

1752

2190

<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:

0.00723

AC:

1100

AN:

152232

Hom.:

Cov.:

AF XY:

0.00717

AC XY:

534

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.00176

AC:

AN:

41528

American (AMR)

AF:

0.00628

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00576

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5186

South Asian (SAS)

AF:

0.00828

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00517

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.0408

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0116

AC:

786

AN:

67988

Other (OTH)

AF:

0.00805

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

114

171

228

285

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00935

Hom.:

Bravo

AF:

0.00642

TwinsUK

AF:

0.00863

AC:

ALSPAC

AF:

0.0104

AC:

ESP6500AA

AF:

0.00272

AC:

ESP6500EA

AF:

0.0113

AC:

ExAC

AF:

0.00796

AC:

966

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.0101

EpiControl

AF:

0.0106

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Immunodeficiency 35 (2)

not provided (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.14

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.33

Eigen

Uncertain

0.34

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.88

MetaRNN

Benign

0.0094

MetaSVM

Uncertain

0.014

MutationAssessor

Uncertain

2.9

PhyloP100

4.5

PrimateAI

Uncertain

0.60

PROVEAN

Uncertain

-3.2

REVEL

Uncertain

0.46

Sift

Benign

0.033

Sift4G

Uncertain

0.0040

Polyphen

1.0

Vest4

0.63

MVP

0.83

MPC

0.92

ClinPred

0.012

GERP RS

4.7

PromoterAI

-0.023

Neutral

(source)

Varity_R

0.40

gMVP

0.82

Mutation Taster

=95/5

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

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over