rs760895143

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The NM_003331.5(TYK2):c.1106C>T(p.Pro369Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000551 in 1,613,988 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P369P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000060 ( 0 hom. )

Consequence

TYK2
NM_003331.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: -0.447

Publications

4 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: Likely_benign. The variant received -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.04107523).

BP6

Variant 19-10364954-G-A is Benign according to our data. Variant chr19-10364954-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 430205.

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.1106C>T	p.Pro369Leu	missense	Exon 8 of 25	NP_003322.3
TYK2	NM_001385204.1		c.1106C>T	p.Pro369Leu	missense	Exon 8 of 25	NP_001372133.1
TYK2	NM_001385203.1		c.1106C>T	p.Pro369Leu	missense	Exon 8 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.1106C>T	p.Pro369Leu	missense	Exon 8 of 25	ENSP00000431885.1	P29597
TYK2	ENST00000524462.5	TSL:1	c.551C>T	p.Pro184Leu	missense	Exon 4 of 21	ENSP00000433203.1	E9PM19
TYK2	ENST00000531836.7	TSL:4	c.1106C>T	p.Pro369Leu	missense	Exon 8 of 25	ENSP00000436175.2	P29597

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152250

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000398

AC:

AN:

251086

AF XY:

0.0000221

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000595

AC:

AN:

1461738

Hom.:

Cov.:

AF XY:

0.0000619

AC XY:

AN XY:

727202

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33480

American (AMR)

AF:

0.000179

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000162

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53280

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000549

AC:

AN:

1112002

Other (OTH)

AF:

0.0000497

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152250

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74388

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41472

American (AMR)

AF:

0.0000654

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68036

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.0000330

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.0000494

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Immunodeficiency 35 (1)

Inborn genetic diseases (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.67

CADD

Benign

2.9

(source)

DANN

Benign

0.43

DEOGEN2

Benign

0.072

Eigen

Benign

-1.9

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.67

M_CAP

Benign

0.0068

MetaRNN

Benign

0.041

MetaSVM

Benign

-0.94

MutationAssessor

Benign

1.9

PhyloP100

-0.45

PrimateAI

Benign

0.31

PROVEAN

Benign

-1.0

REVEL

Benign

0.019

Sift

Benign

0.39

Sift4G

Benign

0.35

Polyphen

0.0020

Vest4

0.14

MVP

0.13

MPC

0.27

ClinPred

0.018

GERP RS

-0.98

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.025

gMVP

0.27

Mutation Taster

=94/6

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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