rs280521

chr19-10362716-G-A

Variant summary

Our verdict is Benign. Variant got -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:2
• Conservation: PhyloP100: 1.28

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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/exons	MANE	UniProt
TYK2	NM_003331.5	c.1368-59C>T		intron_variant		ENST00000525621.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TYK2	ENST00000525621.6	c.1368-59C>T		intron_variant		1	NM_003331.5	P1

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

Gnomad4 AFR exome AF: 0.263

Gnomad4 AMR exome AF: 0.0810

Gnomad4 ASJ exome AF: 0.112

Gnomad4 EAS exome AF: 0.0184

Gnomad4 SAS exome AF: 0.148

Gnomad4 FIN exome AF: 0.145

Gnomad4 NFE exome AF: 0.147

Gnomad4 OTH exome AF: 0.142

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

Gnomad4 AFR AF: 0.259

Gnomad4 AMR AF: 0.109

Gnomad4 ASJ AF: 0.118

Gnomad4 EAS AF: 0.0269

Gnomad4 SAS AF: 0.138

Gnomad4 FIN AF: 0.141

Gnomad4 NFE AF: 0.146

Gnomad4 OTH AF: 0.152

Alfa AF: 0.160 Hom.: 330

Bravo AF: 0.170

Asia WGS AF: 0.102 AC: 354 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Nov 12, 2023

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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 19, 2018

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
BayesDel_noAF	Benign	-0.88
Cadd	Benign	5.8
Dann	Benign	0.31
RBP_binding_hub_radar		0.67
RBP_regulation_power_radar		1.8

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

Other links and lift over

dbSNP: rs280521; hg19: chr19-10473392;