rs34536443

Positions:

chr19-10352442-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_003331.5(TYK2):c.3310C>G(p.Pro1104Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0371 in 1,607,098 control chromosomes in the GnomAD database, including 1,233 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.028 ( 69 hom., cov: 32)

Exomes 𝑓: 0.038 ( 1164 hom. )

Consequence

TYK2
NM_003331.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1B:7

Conservation

PhyloP100: 7.51

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009062827).

BP6

Variant 19-10352442-G-C is Benign according to our data. Variant chr19-10352442-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 137869.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-10352442-G-C is described in Lovd as [Likely_benign]. Variant chr19-10352442-G-C is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0278 (4238/152278) while in subpopulation NFE AF= 0.044 (2990/68018). AF 95% confidence interval is 0.0426. There are 69 homozygotes in gnomad4. There are 1983 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 69 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TYK2	NM_003331.5 linkuse as main transcript	c.3310C>G	p.Pro1104Ala	missense_variant	23/25	ENST00000525621.6	NP_003322.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TYK2	ENST00000525621.6 linkuse as main transcript	c.3310C>G	p.Pro1104Ala	missense_variant	23/25	1	NM_003331.5	ENSP00000431885	P1

Frequencies

GnomAD3 genomes

AF:

0.0278

AC:

4235

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00914

Gnomad AMI

AF:

0.0143

Gnomad AMR

AF:

0.0214

Gnomad ASJ

AF:

0.0332

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0114

Gnomad FIN

AF:

0.0287

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0439

Gnomad OTH

AF:

0.0206

GnomAD3 exomes

AF:

0.0268

AC:

6632

AN:

247438

Hom.:

123

AF XY:

0.0271

AC XY:

3628

AN XY:

133876

show subpopulations

Gnomad AFR exome

AF:

0.00712

Gnomad AMR exome

AF:

0.0120

Gnomad ASJ exome

AF:

0.0301

Gnomad EAS exome

AF:

0.0000551

Gnomad SAS exome

AF:

0.0111

Gnomad FIN exome

AF:

0.0311

Gnomad NFE exome

AF:

0.0417

Gnomad OTH exome

AF:

0.0251

GnomAD4 exome

AF:

0.0381

AC:

55360

AN:

1454820

Hom.:

1164

Cov.:

AF XY:

0.0371

AC XY:

26862

AN XY:

723964

show subpopulations

Gnomad4 AFR exome

AF:

0.00703

Gnomad4 AMR exome

AF:

0.0123

Gnomad4 ASJ exome

AF:

0.0305

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0115

Gnomad4 FIN exome

AF:

0.0300

Gnomad4 NFE exome

AF:

0.0445

Gnomad4 OTH exome

AF:

0.0299

GnomAD4 genome

AF:

0.0278

AC:

4238

AN:

152278

Hom.:

Cov.:

AF XY:

0.0266

AC XY:

1983

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.00912

Gnomad4 AMR

AF:

0.0214

Gnomad4 ASJ

AF:

0.0332

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0118

Gnomad4 FIN

AF:

0.0287

Gnomad4 NFE

AF:

0.0440

Gnomad4 OTH

AF:

0.0204

Alfa

AF:

0.0382

Hom.:

Bravo

AF:

0.0262

TwinsUK

AF:

0.0475

AC:

176

ALSPAC

AF:

0.0527

AC:

203

ESP6500AA

AF:

0.00681

AC:

ESP6500EA

AF:

0.0403

AC:

347

ExAC

AF:

0.0268

AC:

3256

Asia WGS

AF:

0.00635

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Immunodeficiency 35

Pathogenic:1Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 26, 2021	- -

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 28, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.83

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Uncertain

-0.070

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.46

T;D;T

Eigen

Uncertain

0.67

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.94

D;D;.

MetaRNN

Benign

0.0091

T;T;T

MetaSVM

Uncertain

-0.060

MutationAssessor

Benign

1.4

L;.;L

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.57

PROVEAN

Pathogenic

-6.8

D;D;D

REVEL

Uncertain

0.59

Sift

Uncertain

0.0020

D;D;D

Sift4G

Uncertain

0.0070

D;D;D

Polyphen

1.0

D;.;D

Vest4

0.22

MPC

0.81

ClinPred

0.028

GERP RS

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.68

gMVP

0.67

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over