chr19-10362257-A-G

Position:

chr19-10362257-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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/exons	MANE	Protein	UniProt
TYK2	NM_003331.5 linkuse as main transcript	c.1669+7T>C		splice_region_variant, intron_variant		ENST00000525621.6	NP_003322.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TYK2	ENST00000525621.6 linkuse as main transcript	c.1669+7T>C		splice_region_variant, intron_variant		1	NM_003331.5	ENSP00000431885	P1

Frequencies

GnomAD3 genomes

AF:

0.519

AC:

78757

AN:

151768

Hom.:

20764

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.516

AC XY:

374865

AN XY:

727132

show subpopulations

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.:

AF XY:

0.516

AC XY:

38291

AN XY:

74206

show subpopulations

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

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	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 -
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 66% of patients studied by a panel of primary immunodeficiencies. Number of patients: 63. Only high quality variants are reported. -

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Immunodeficiency 35

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over