rs280521

Variant names:

• chr19-10362716-G-A
• rs280521
• NM_003331.5:c.1368-59C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003331.5(TYK2):​c.1368-59C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.146 in 1,429,234 control chromosomes in the GnomAD database, including 16,395 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2401 hom., cov: 32)
  • Exomes 𝑓: 0.14 (13994 hom.)
• Consequence: TYK2 NM_003331.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.28
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 19-10362716-G-A is Benign according to our data. Variant chr19-10362716-G-A is described in ClinVar as Benign. ClinVar VariationId is 673299.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.255 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TYK2	NM_003331.5	c.1368-59C>T		intron_variant	Intron 9 of 24	ENST00000525621.6	NP_003322.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TYK2	ENST00000525621.6	c.1368-59C>T		intron_variant	Intron 9 of 24	1	NM_003331.5	ENSP00000431885.1

Frequencies

GnomAD3 genomes AF: 0.168 AC: 25506 AN: 151970 Hom.: 2392 Cov.: 32

Gnomad AFR AF: 0.259

Gnomad AMI AF: 0.152

Gnomad AMR AF: 0.109

Gnomad ASJ AF: 0.118

Gnomad EAS AF: 0.0270

Gnomad SAS AF: 0.140

Gnomad FIN AF: 0.141

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.146

Gnomad OTH AF: 0.148

GnomAD4 exome AF: 0.143 AC: 183058 AN: 1277144 Hom.: 13994 AF XY: 0.143 AC XY: 90721 AN XY: 634604

African (AFR) AF: 0.263 AC: 7664 AN: 29098

American (AMR) AF: 0.0810 AC: 2876 AN: 35488

Ashkenazi Jewish (ASJ) AF: 0.112 AC: 2743 AN: 24442

East Asian (EAS) AF: 0.0184 AC: 647 AN: 35220

South Asian (SAS) AF: 0.148 AC: 11374 AN: 76734

European-Finnish (FIN) AF: 0.145 AC: 6815 AN: 47158

Middle Eastern (MID) AF: 0.128 AC: 548 AN: 4270

European-Non Finnish (NFE) AF: 0.147 AC: 142738 AN: 970910

Other (OTH) AF: 0.142 AC: 7653 AN: 53824

GnomAD4 genome AF: 0.168 AC: 25547 AN: 152090 Hom.: 2401 Cov.: 32 AF XY: 0.165 AC XY: 12264 AN XY: 74354

African (AFR) AF: 0.259 AC: 10735 AN: 41456

American (AMR) AF: 0.109 AC: 1665 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.118 AC: 408 AN: 3468

East Asian (EAS) AF: 0.0269 AC: 139 AN: 5172

South Asian (SAS) AF: 0.138 AC: 668 AN: 4826

European-Finnish (FIN) AF: 0.141 AC: 1489 AN: 10586

Middle Eastern (MID) AF: 0.129 AC: 38 AN: 294

European-Non Finnish (NFE) AF: 0.146 AC: 9945 AN: 67992

Other (OTH) AF: 0.152 AC: 321 AN: 2116

Alfa AF: 0.162 Hom.: 354

Bravo AF: 0.170

Asia WGS AF: 0.102 AC: 354 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 19, 2018

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. -

not specified Benign:1

Nov 12, 2023

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 21% of patients studied by a panel of primary immunodeficiencies. Number of patients: 20. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	5.8
DANN	Benign	0.31
PhyloP100		1.3
RBP_binding_hub_radar		0.67
RBP_regulation_power_radar		1.8
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs280521; hg19: chr19-10473392;