19-10362257-A-G

Variant names:

• chr19-10362257-A-G
• rs280519
• NM_003331.5:c.1669+7T>C

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.1669+7T>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 0.516 in 1,613,552 control chromosomes in the GnomAD database, including 217,520 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 0.52 (20801 hom., cov: 31)
  • Exomes 𝑓: 0.52 (196719 hom.)
• Consequence: TYK2 NM_003331.5 splice_region, intron
• Scores: Splicing: ADA: 0.00001091
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -3.11

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=-0.91).
• BP6: Variant 19-10362257-A-G is Benign according to our data. Variant chr19-10362257-A-G is described in ClinVar as [Benign]. Clinvar id is 259041.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-10362257-A-G is described in Lovd as [Benign]. Variant chr19-10362257-A-G is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.573 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TYK2	NM_003331.5	c.1669+7T>C		splice_region_variant, intron_variant	Intron 11 of 24	ENST00000525621.6	NP_003322.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TYK2	ENST00000525621.6	c.1669+7T>C		splice_region_variant, intron_variant	Intron 11 of 24	1	NM_003331.5	ENSP00000431885.1

Frequencies

GnomAD3 genomes AF: 0.519 AC: 78757 AN: 151768 Hom.: 20764 Cov.: 31

Gnomad AFR AF: 0.565

Gnomad AMI AF: 0.585

Gnomad AMR AF: 0.408

Gnomad ASJ AF: 0.536

Gnomad EAS AF: 0.590

Gnomad SAS AF: 0.530

Gnomad FIN AF: 0.524

Gnomad MID AF: 0.566

Gnomad NFE AF: 0.507

Gnomad OTH AF: 0.505

GnomAD3 exomes AF: 0.501 AC: 125522 AN: 250748 Hom.: 32389 AF XY: 0.504 AC XY: 68353 AN XY: 135558

Gnomad AFR exome AF: 0.568

Gnomad AMR exome AF: 0.319

Gnomad ASJ exome AF: 0.520

Gnomad EAS exome AF: 0.605

Gnomad SAS exome AF: 0.518

Gnomad FIN exome AF: 0.533

Gnomad NFE exome AF: 0.516

Gnomad OTH exome AF: 0.510

GnomAD4 exome AF: 0.516 AC: 754252 AN: 1461666 Hom.: 196719 Cov.: 56 AF XY: 0.516 AC XY: 374865 AN XY: 727132

Gnomad4 AFR exome AF: 0.572

Gnomad4 AMR exome AF: 0.330

Gnomad4 ASJ exome AF: 0.518

Gnomad4 EAS exome AF: 0.520

Gnomad4 SAS exome AF: 0.514

Gnomad4 FIN exome AF: 0.536

Gnomad4 NFE exome AF: 0.520

Gnomad4 OTH exome AF: 0.534

GnomAD4 genome AF: 0.519 AC: 78856 AN: 151886 Hom.: 20801 Cov.: 31 AF XY: 0.516 AC XY: 38291 AN XY: 74206

Gnomad4 AFR AF: 0.565

Gnomad4 AMR AF: 0.409

Gnomad4 ASJ AF: 0.536

Gnomad4 EAS AF: 0.590

Gnomad4 SAS AF: 0.529

Gnomad4 FIN AF: 0.524

Gnomad4 NFE AF: 0.507

Gnomad4 OTH AF: 0.508

Alfa AF: 0.506 Hom.: 15822

Bravo AF: 0.516

Asia WGS AF: 0.565 AC: 1959 AN: 3478

EpiCase AF: 0.515

EpiControl AF: 0.510

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

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 66% of patients studied by a panel of primary immunodeficiencies. Number of patients: 63. Only high quality variants are reported. -

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:3

-

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

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Immunodeficiency 35 Benign:3

Jan 12, 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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.069
DANN	Benign	0.35

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000011
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.070		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: rs280519; hg19: chr19-10472933; COSMIC: COSV53384683; COSMIC: COSV53384683;