rs280520

chr19-10362462-A-G

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.1477-6T>C variant causes a splice region, splice polypyrimidine tract, 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, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00004761
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -6.71

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=-0.92).
• BP6: Variant 19-10362462-A-G is Benign according to our data. Variant chr19-10362462-A-G is described in ClinVar as [Benign]. Clinvar id is 137865.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-10362462-A-G is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
TYK2	NM_003331.5	c.1477-6T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000525621.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TYK2	ENST00000525621.6	c.1477-6T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_003331.5	P1

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

GnomAD3 exomes AF: 0.264 AC: 56952 AN: 216126 Hom.: 7863 AF XY: 0.264 AC XY: 30783 AN XY: 116784

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 SAS exome AF: 0.315

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

Gnomad4 AFR exome AF: 0.390

Gnomad4 AMR exome AF: 0.197

Gnomad4 ASJ exome AF: 0.214

Gnomad4 EAS exome AF: 0.401

Gnomad4 SAS exome AF: 0.314

Gnomad4 FIN exome AF: 0.288

Gnomad4 NFE exome AF: 0.230

Gnomad4 OTH exome AF: 0.266

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

Gnomad4 AFR AF: 0.379

Gnomad4 AMR AF: 0.220

Gnomad4 ASJ AF: 0.215

Gnomad4 EAS AF: 0.425

Gnomad4 SAS AF: 0.329

Gnomad4 FIN AF: 0.290

Gnomad4 NFE AF: 0.225

Gnomad4 OTH AF: 0.273

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:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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 43% of patients studied by a panel of primary immunodeficiencies. Number of patients: 41. Only high quality variants are reported. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 27, 2013	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. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Immunodeficiency 35 Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
Cadd	Benign	0.072
Dann	Benign	0.32

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

Publications

LitVar

Other links and lift over

dbSNP: rs280520; hg19: chr19-10473138; COSMIC: COSV53384706; COSMIC: COSV53384706;