19-10354011-A-G

Variant names:

• chr19-10354011-A-G
• rs280497
• NM_003331.5:c.2908+31T>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.2908+31T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.535 in 1,610,030 control chromosomes in the GnomAD database, including 232,452 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.56 (23886 hom., cov: 33)
  • Exomes 𝑓: 0.53 (208566 hom.)
• Consequence: TYK2 NM_003331.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.76
• Publications: 22 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=-0.82).
• BP6: Variant 19-10354011-A-G is Benign according to our data. Variant chr19-10354011-A-G is described in ClinVar as Benign. ClinVar VariationId is 673300.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.633 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TYK2	NM_003331.5	c.2908+31T>C		intron_variant	Intron 20 of 24	ENST00000525621.6	NP_003322.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TYK2	ENST00000525621.6	c.2908+31T>C		intron_variant	Intron 20 of 24	1	NM_003331.5	ENSP00000431885.1

Frequencies

GnomAD3 genomes AF: 0.556 AC: 84405 AN: 151810 Hom.: 23842 Cov.: 33

Gnomad AFR AF: 0.639

Gnomad AMI AF: 0.590

Gnomad AMR AF: 0.484

Gnomad ASJ AF: 0.563

Gnomad EAS AF: 0.636

Gnomad SAS AF: 0.542

Gnomad FIN AF: 0.532

Gnomad MID AF: 0.586

Gnomad NFE AF: 0.520

Gnomad OTH AF: 0.530

GnomAD2 exomes AF: 0.527 AC: 131111 AN: 248602 AF XY: 0.527

Gnomad AFR exome AF: 0.640

Gnomad AMR exome AF: 0.398

Gnomad ASJ exome AF: 0.551

Gnomad EAS exome AF: 0.651

Gnomad FIN exome AF: 0.537

Gnomad NFE exome AF: 0.528

Gnomad OTH exome AF: 0.525

GnomAD4 exome AF: 0.533 AC: 776476 AN: 1458102 Hom.: 208566 Cov.: 33 AF XY: 0.531 AC XY: 385216 AN XY: 725498

African (AFR) AF: 0.648 AC: 21661 AN: 33428

American (AMR) AF: 0.410 AC: 18340 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.548 AC: 14295 AN: 26106

East Asian (EAS) AF: 0.570 AC: 22599 AN: 39662

South Asian (SAS) AF: 0.519 AC: 44688 AN: 86168

European-Finnish (FIN) AF: 0.540 AC: 28401 AN: 52620

Middle Eastern (MID) AF: 0.569 AC: 3223 AN: 5666

European-Non Finnish (NFE) AF: 0.532 AC: 589984 AN: 1109476

Other (OTH) AF: 0.552 AC: 33285 AN: 60288

GnomAD4 genome AF: 0.556 AC: 84508 AN: 151928 Hom.: 23886 Cov.: 33 AF XY: 0.554 AC XY: 41162 AN XY: 74276

African (AFR) AF: 0.640 AC: 26521 AN: 41452

American (AMR) AF: 0.485 AC: 7381 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.563 AC: 1952 AN: 3466

East Asian (EAS) AF: 0.636 AC: 3272 AN: 5146

South Asian (SAS) AF: 0.541 AC: 2608 AN: 4824

European-Finnish (FIN) AF: 0.532 AC: 5627 AN: 10576

Middle Eastern (MID) AF: 0.592 AC: 173 AN: 292

European-Non Finnish (NFE) AF: 0.520 AC: 35319 AN: 67924

Other (OTH) AF: 0.531 AC: 1118 AN: 2104

Alfa AF: 0.489 Hom.: 3951

Bravo AF: 0.558

Asia WGS AF: 0.585 AC: 2030 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 14, 2018

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 specified Benign:1

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 77% of patients studied by a panel of primary immunodeficiencies. Number of patients: 74. Only high quality variants are reported. -

Immunodeficiency 35 Benign:1

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	-0.82
CADD	Benign	0.35
DANN	Benign	0.27
PhyloP100		-1.8
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs280497; hg19: chr19-10464687; COSMIC: COSV53385733; COSMIC: COSV53385733;