rs12720356

Positions:

Variant summary

Our verdict is Benign. Variant got -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 (★★).

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

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 -14 ACMG points.

PP3

Splicing scoreres supports a deletorius 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 id is 259043.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-10359299-A-C is described in Lovd as [Likely_benign].

BA1

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TYK2	NM_003331.5 linkuse as main transcript	c.2051T>G	p.Ile684Ser	missense_variant	15/25	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.2051T>G	p.Ile684Ser	missense_variant	15/25	1	NM_003331.5	ENSP00000431885	P1

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

GnomAD3 exomes

AF:

0.0608

AC:

15034

AN:

247106

Hom.:

670

AF XY:

0.0605

AC XY:

8122

AN XY:

134200

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 SAS exome

AF:

0.00882

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

Gnomad4 AFR exome

AF:

0.0128

Gnomad4 AMR exome

AF:

0.0390

Gnomad4 ASJ exome

AF:

0.100

Gnomad4 EAS exome

AF:

0.000176

Gnomad4 SAS exome

AF:

0.00993

Gnomad4 FIN exome

AF:

0.0835

Gnomad4 NFE exome

AF:

0.0942

Gnomad4 OTH exome

AF:

0.0774

GnomAD4 genome

AF:

0.0573

AC:

8721

AN:

152230

Hom.:

346

Cov.:

AF XY:

0.0553

AC XY:

4118

AN XY:

74418

show subpopulations

Gnomad4 AFR

AF:

0.0152

Gnomad4 AMR

AF:

0.0533

Gnomad4 ASJ

AF:

0.0963

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00913

Gnomad4 FIN

AF:

0.0823

Gnomad4 NFE

AF:

0.0858

Gnomad4 OTH

AF:

0.0568

Alfa

AF:

0.0782

Hom.:

1271

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

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: MAF -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 21085059, 28973304, 27807284, 15657875, 25849893, 20953190, 23143594, 23359498, 18270328) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Immunodeficiency 35

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.59

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Uncertain

-0.040

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.47

T;T;T;.

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

D;D;.;D

MetaRNN

Benign

0.0056

T;T;T;T

MetaSVM

Benign

-0.73

MutationAssessor

Uncertain

2.4

M;.;M;.

MutationTaster

Benign

3.0e-7

P;P;P;P

PrimateAI

Uncertain

0.61

PROVEAN

Pathogenic

-5.1

D;D;D;D

REVEL

Uncertain

0.34

Sift

Uncertain

0.0070

D;D;D;D

Sift4G

Uncertain

0.0060

D;D;D;D

Polyphen

1.0

D;.;D;D

Vest4

0.33

MPC

1.1

ClinPred

0.035

GERP RS

3.7

Varity_R

0.74

gMVP

0.90

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

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