rs280520

Variant names:

• chr19-10362462-A-G
• rs280520
• NM_003331.5:c.1477-6T>C

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.1477-6T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.249 in 1,591,026 control chromosomes in the GnomAD database, including 51,487 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (6416 hom., cov: 32)
  • Exomes 𝑓: 0.25 (45071 hom.)
• Consequence: TYK2 NM_003331.5 splice_region, intron
• Scores: Splicing: ADA: 0.00004761
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -6.71
• Publications: 20 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=-0.92).
• BP6: Variant 19-10362462-A-G is Benign according to our data. Variant chr19-10362462-A-G is described in ClinVar as Benign. ClinVar VariationId is 137865.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.41 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TYK2	NM_003331.5	c.1477-6T>C		splice_region_variant, intron_variant	Intron 10 of 24	ENST00000525621.6	NP_003322.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TYK2	ENST00000525621.6	c.1477-6T>C		splice_region_variant, intron_variant	Intron 10 of 24	1	NM_003331.5	ENSP00000431885.1

Frequencies

GnomAD3 genomes AF: 0.281 AC: 42697 AN: 151858 Hom.: 6396 Cov.: 32

Gnomad AFR AF: 0.379

Gnomad AMI AF: 0.164

Gnomad AMR AF: 0.220

Gnomad ASJ AF: 0.215

Gnomad EAS AF: 0.425

Gnomad SAS AF: 0.330

Gnomad FIN AF: 0.290

Gnomad MID AF: 0.285

Gnomad NFE AF: 0.225

Gnomad OTH AF: 0.269

GnomAD2 exomes AF: 0.264 AC: 56952 AN: 216126 AF XY: 0.264

Gnomad AFR exome AF: 0.381

Gnomad AMR exome AF: 0.194

Gnomad ASJ exome AF: 0.216

Gnomad EAS exome AF: 0.421

Gnomad FIN exome AF: 0.294

Gnomad NFE exome AF: 0.227

Gnomad OTH exome AF: 0.255

GnomAD4 exome AF: 0.246 AC: 353344 AN: 1439048 Hom.: 45071 Cov.: 39 AF XY: 0.247 AC XY: 175862 AN XY: 713318

African (AFR) AF: 0.390 AC: 12893 AN: 33092

American (AMR) AF: 0.197 AC: 8114 AN: 41168

Ashkenazi Jewish (ASJ) AF: 0.214 AC: 5469 AN: 25614

East Asian (EAS) AF: 0.401 AC: 15537 AN: 38730

South Asian (SAS) AF: 0.314 AC: 26374 AN: 83932

European-Finnish (FIN) AF: 0.288 AC: 14886 AN: 51754

Middle Eastern (MID) AF: 0.265 AC: 1518 AN: 5720

European-Non Finnish (NFE) AF: 0.230 AC: 252740 AN: 1099564

Other (OTH) AF: 0.266 AC: 15813 AN: 59474

GnomAD4 genome AF: 0.281 AC: 42773 AN: 151978 Hom.: 6416 Cov.: 32 AF XY: 0.284 AC XY: 21070 AN XY: 74274

African (AFR) AF: 0.379 AC: 15719 AN: 41460

American (AMR) AF: 0.220 AC: 3356 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.215 AC: 746 AN: 3470

East Asian (EAS) AF: 0.425 AC: 2192 AN: 5156

South Asian (SAS) AF: 0.329 AC: 1582 AN: 4814

European-Finnish (FIN) AF: 0.290 AC: 3067 AN: 10562

Middle Eastern (MID) AF: 0.282 AC: 83 AN: 294

European-Non Finnish (NFE) AF: 0.225 AC: 15304 AN: 67944

Other (OTH) AF: 0.273 AC: 575 AN: 2106

Alfa AF: 0.239 Hom.: 1832

Bravo AF: 0.282

Asia WGS AF: 0.405 AC: 1402 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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 43% of patients studied by a panel of primary immunodeficiencies. Number of patients: 41. Only high quality variants are reported.

Sep 27, 2013

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.

Immunodeficiency 35 Benign:3

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.072
DANN	Benign	0.32
PhyloP100		-6.7
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000048
dbscSNV1_RF	Benign	0.0
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: rs280520; hg19: chr19-10473138; COSMIC: COSV53384706; COSMIC: COSV53384706;