dbSNP rs280501: TYK2:c.-452G>A (chr19-10380646-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_003331.5(TYK2):c.-452G>A variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.199 in 151,158 control chromosomes in the GnomAD database, including 3,549 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.20 ( 3549 hom., cov: 31)

Exomes 𝑓: 0.075 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TYK2
NM_003331.5 upstream_gene

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.36

Publications

16 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.79).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.323 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TYK2	NM_003331.5 link	c.-452G>A		upstream_gene_variant		ENST00000525621.6	NP_003322.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TYK2	ENST00000525621.6 link	c.-452G>A		upstream_gene_variant		1	NM_003331.5	ENSP00000431885.1

Frequencies

GnomAD3 genomes

AF:

0.199

AC:

30043

AN:

151050

Hom.:

3533

Cov.:

show subpopulations

Gnomad AFR

AF:

0.327

Gnomad AMI

AF:

0.0938

Gnomad AMR

AF:

0.130

Gnomad ASJ

AF:

0.166

Gnomad EAS

AF:

0.0380

Gnomad SAS

AF:

0.188

Gnomad FIN

AF:

0.181

Gnomad MID

AF:

0.242

Gnomad NFE

AF:

0.155

Gnomad OTH

AF:

0.184

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0747

AC:

AN:

174

Hom.:

Cov.:

AF XY:

0.0849

AC XY:

AN XY:

106

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AF:

0.0847

AC:

AN:

118

South Asian (SAS)

AF:

0.0500

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0625

AC:

AN:

Other (OTH)

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

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:

0.199

AC:

30102

AN:

151158

Hom.:

3549

Cov.:

AF XY:

0.197

AC XY:

14510

AN XY:

73770

show subpopulations

African (AFR)

AF:

0.328

AC:

13497

AN:

41190

American (AMR)

AF:

0.130

AC:

1969

AN:

15184

Ashkenazi Jewish (ASJ)

AF:

0.166

AC:

576

AN:

3470

East Asian (EAS)

AF:

0.0379

AC:

191

AN:

5042

South Asian (SAS)

AF:

0.188

AC:

894

AN:

4756

European-Finnish (FIN)

AF:

0.181

AC:

1880

AN:

10380

Middle Eastern (MID)

AF:

0.240

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.155

AC:

10545

AN:

67832

Other (OTH)

AF:

0.188

AC:

395

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

1154

2307

3461

4614

5768

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

304

608

912

1216

1520

<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:

0.166

Hom.:

7855

Bravo

AF:

0.199

Asia WGS

AF:

0.139

AC:

480

AN:

3470

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

1.2

(source)

DANN

Benign

0.68

PhyloP100

-1.4

PromoterAI

0.019

Neutral

(source)

Mutation Taster

=300/0

polymorphism (auto)

(source)

Splicing

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over