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: Labcorp Genetics (formerly Invitae), Orphanet

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.

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	Effect	Exon Rank	Protein
TYK2	NM_003331.5	MANE Select	c.-452G>A	upstream_gene	N/A	NP_003322.3
TYK2	NM_001385204.1		c.-452G>A	upstream_gene	N/A	NP_001372133.1
TYK2	NM_001385203.1		c.-452G>A	upstream_gene	N/A	NP_001372132.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TYK2	ENST00000525621.6	TSL:1 MANE Select	c.-452G>A	upstream_gene	N/A	ENSP00000431885.1	P29597
TYK2	ENST00000524462.5	TSL:1	c.-227G>A	upstream_gene	N/A	ENSP00000433203.1	E9PM19
TYK2	ENST00000531836.7	TSL:4	c.-362G>A	upstream_gene	N/A	ENSP00000436175.2	P29597

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 v4.9

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over