19-10361959-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_003331.5(TYK2):c.1774-4G>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 0.00759 in 1,613,930 control chromosomes in the GnomAD database, including 775 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 0.040 ( 389 hom., cov: 32)

Exomes 𝑓: 0.0042 ( 386 hom. )

Consequence

TYK2
NM_003331.5 splice_region, intron

Scores

Splicing: ADA: 0.0001158

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.761

Publications

5 publications found

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 Gene-Disease associations (from GenCC):

immunodeficiency 35
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

TYK2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BP6

Variant 19-10361959-C-G is Benign according to our data. Variant chr19-10361959-C-G is described in ClinVar as [Benign]. Clinvar id is 137866.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.137 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TYK2	NM_003331.5 link	c.1774-4G>C		splice_region_variant, intron_variant	Intron 12 of 24	ENST00000525621.6	NP_003322.3	P29597A0A024R7E4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TYK2	ENST00000525621.6 link	c.1774-4G>C		splice_region_variant, intron_variant	Intron 12 of 24	1	NM_003331.5	ENSP00000431885.1		P29597

Frequencies

GnomAD3 genomes

AF:

0.0404

AC:

6136

AN:

152038

Hom.:

389

Cov.:

show subpopulations

Gnomad AFR

AF:

0.140

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0148

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000441

Gnomad OTH

AF:

0.0282

GnomAD2 exomes

AF:

0.0109

AC:

2740

AN:

250838

AF XY:

0.00812

show subpopulations

Gnomad AFR exome

AF:

0.148

Gnomad AMR exome

AF:

0.00773

Gnomad ASJ exome

AF:

0.00169

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000309

Gnomad OTH exome

AF:

0.00441

GnomAD4 exome

AF:

0.00418

AC:

6110

AN:

1461774

Hom.:

386

Cov.:

AF XY:

0.00354

AC XY:

2577

AN XY:

727204

show subpopulations

African (AFR)

AF:

0.148

AC:

4963

AN:

33480

American (AMR)

AF:

0.00823

AC:

368

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00122

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000220

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000562

AC:

AN:

53340

Middle Eastern (MID)

AF:

0.00347

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000192

AC:

214

AN:

1111982

Other (OTH)

AF:

0.00813

AC:

491

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

355

709

1064

1418

1773

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0404

AC:

6146

AN:

152156

Hom.:

389

Cov.:

AF XY:

0.0394

AC XY:

2928

AN XY:

74388

show subpopulations

African (AFR)

AF:

0.140

AC:

5821

AN:

41470

American (AMR)

AF:

0.0148

AC:

226

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00173

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.000622

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000441

AC:

AN:

68000

Other (OTH)

AF:

0.0279

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

270

541

811

1082

1352

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00235

Hom.:

Bravo

AF:

0.0467

Asia WGS

AF:

0.00751

AC:

AN:

3478

EpiCase

AF:

0.000382

EpiControl

AF:

0.000711

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Immunodeficiency 35

Benign:2

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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. -

not specified

Benign:1

Mar 11, 2014

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. -

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

-0.87

CADD

Benign

1.7

(source)

DANN

Benign

0.38

PhyloP100

-0.76

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00012

dbscSNV1_RF

Benign

0.046

SpliceAI score (max)

0.16

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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19-10361959-C-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over