chr19-10378250-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -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

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=0.0094073415).

BP6

Variant 19-10378250-C-T is Benign according to our data. Variant chr19-10378250-C-T is described in ClinVar as [Benign]. Clinvar id is 378838.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-10378250-C-T is described in Lovd as [Likely_benign].

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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TYK2	NM_003331.5 link	c.157G>A	p.Ala53Thr	missense_variant	Exon 3 of 25	ENST00000525621.6	NP_003322.3	P29597A0A024R7E4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TYK2	ENST00000525621.6 link	c.157G>A	p.Ala53Thr	missense_variant	Exon 3 of 25	1	NM_003331.5	ENSP00000431885.1		P29597

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

GnomAD3 exomes

AF:

0.00735

AC:

1839

AN:

250170

Hom.:

AF XY:

0.00785

AC XY:

1065

AN XY:

135708

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 SAS exome

AF:

0.00807

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

Gnomad4 AFR exome

AF:

0.00122

Gnomad4 AMR exome

AF:

0.00369

Gnomad4 ASJ exome

AF:

0.00517

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00865

Gnomad4 FIN exome

AF:

0.00537

Gnomad4 NFE exome

AF:

0.0108

Gnomad4 OTH exome

AF:

0.00752

GnomAD4 genome

AF:

0.00723

AC:

1100

AN:

152232

Hom.:

Cov.:

AF XY:

0.00717

AC XY:

534

AN XY:

74436

show subpopulations

Gnomad4 AFR

AF:

0.00176

Gnomad4 AMR

AF:

0.00628

Gnomad4 ASJ

AF:

0.00576

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00828

Gnomad4 FIN

AF:

0.00517

Gnomad4 NFE

AF:

0.0116

Gnomad4 OTH

AF:

0.00805

Alfa

AF:

0.00990

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

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TYK2: BS1, BS2 -

Immunodeficiency 35

Benign:2

Jan 26, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not specified

Benign:1

Jun 23, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.14

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.33

T;T;.;.;T

Eigen

Uncertain

0.34

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.88

D;.;D;D;D

MetaRNN

Benign

0.0094

T;T;T;T;T

MetaSVM

Uncertain

0.014

MutationAssessor

Uncertain

2.9

M;M;.;.;.

PrimateAI

Uncertain

0.60

PROVEAN

Uncertain

-3.2

D;D;D;D;N

REVEL

Uncertain

0.46

Sift

Benign

0.033

D;D;D;D;D

Sift4G

Uncertain

0.0040

D;D;D;.;.

Polyphen

1.0

D;D;D;.;.

Vest4

0.63

MVP

0.83

MPC

0.92

ClinPred

0.012

GERP RS

4.7

Varity_R

0.40

gMVP

0.82

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