rs8108236

Variant names:

• chr19-10355156-G-A
• rs8108236
• NM_003331.5:c.2618-547C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003331.5(TYK2):​c.2618-547C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0921 in 152,090 control chromosomes in the GnomAD database, including 685 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 0.092 (685 hom., cov: 31)
• Consequence: TYK2 NM_003331.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.865
• Publications: 15 publications found

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)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.109 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TYK2	NM_003331.5	c.2618-547C>T		intron_variant	Intron 18 of 24	ENST00000525621.6	NP_003322.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TYK2	ENST00000525621.6	c.2618-547C>T		intron_variant	Intron 18 of 24	1	NM_003331.5	ENSP00000431885.1

Frequencies

GnomAD3 genomes AF: 0.0920 AC: 13986 AN: 151972 Hom.: 685 Cov.: 31

Gnomad AFR AF: 0.108

Gnomad AMI AF: 0.0230

Gnomad AMR AF: 0.0687

Gnomad ASJ AF: 0.122

Gnomad EAS AF: 0.0125

Gnomad SAS AF: 0.117

Gnomad FIN AF: 0.107

Gnomad MID AF: 0.165

Gnomad NFE AF: 0.0881

Gnomad OTH AF: 0.101

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0921 AC: 14005 AN: 152090 Hom.: 685 Cov.: 31 AF XY: 0.0923 AC XY: 6864 AN XY: 74352

African (AFR) AF: 0.109 AC: 4504 AN: 41466

American (AMR) AF: 0.0685 AC: 1046 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.122 AC: 422 AN: 3468

East Asian (EAS) AF: 0.0123 AC: 64 AN: 5188

South Asian (SAS) AF: 0.117 AC: 565 AN: 4816

European-Finnish (FIN) AF: 0.107 AC: 1132 AN: 10574

Middle Eastern (MID) AF: 0.163 AC: 48 AN: 294

European-Non Finnish (NFE) AF: 0.0881 AC: 5993 AN: 67994

Other (OTH) AF: 0.0998 AC: 210 AN: 2104

Alfa AF: 0.0907 Hom.: 963

Bravo AF: 0.0893

Asia WGS AF: 0.0840 AC: 292 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	2.9
DANN	Benign	0.64
PhyloP100		0.86
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs8108236; hg19: chr19-10465832;