rs2304256

chr19-10364976-C-A

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.1084G>T(p.Val362Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.276 in 1,613,710 control chromosomes in the GnomAD database, including 64,683 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. V362V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.23 (4829 hom., cov: 34)
  • Exomes 𝑓: 0.28 (59854 hom.)
• Consequence: TYK2 NM_003331.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.133

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 (MetaRNN=1.5118718E-4).
• BP6: Variant 19-10364976-C-A is Benign according to our data. Variant chr19-10364976-C-A is described in ClinVar as [Benign]. Clinvar id is 259040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-10364976-C-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.495 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TYK2	NM_003331.5	c.1084G>T	p.Val362Phe	missense_variant	8/25	ENST00000525621.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TYK2	ENST00000525621.6	c.1084G>T	p.Val362Phe	missense_variant	8/25	1	NM_003331.5	P1

Frequencies

GnomAD3 genomes AF: 0.233 AC: 35442 AN: 152198 Hom.: 4824 Cov.: 34

Gnomad AFR AF: 0.110

Gnomad AMI AF: 0.415

Gnomad AMR AF: 0.226

Gnomad ASJ AF: 0.323

Gnomad EAS AF: 0.511

Gnomad SAS AF: 0.274

Gnomad FIN AF: 0.234

Gnomad MID AF: 0.272

Gnomad NFE AF: 0.278

Gnomad OTH AF: 0.244

GnomAD3 exomes AF: 0.275 AC: 68753 AN: 250350 Hom.: 10480 AF XY: 0.277 AC XY: 37519 AN XY: 135450

Gnomad AFR exome AF: 0.110

Gnomad AMR exome AF: 0.199

Gnomad ASJ exome AF: 0.306

Gnomad EAS exome AF: 0.535

Gnomad SAS exome AF: 0.266

Gnomad FIN exome AF: 0.240

Gnomad NFE exome AF: 0.285

Gnomad OTH exome AF: 0.279

GnomAD4 exome AF: 0.281 AC: 410545 AN: 1461394 Hom.: 59854 Cov.: 50 AF XY: 0.281 AC XY: 204019 AN XY: 727000

Gnomad4 AFR exome AF: 0.103

Gnomad4 AMR exome AF: 0.204

Gnomad4 ASJ exome AF: 0.306

Gnomad4 EAS exome AF: 0.445

Gnomad4 SAS exome AF: 0.263

Gnomad4 FIN exome AF: 0.248

Gnomad4 NFE exome AF: 0.285

Gnomad4 OTH exome AF: 0.290

GnomAD4 genome AF: 0.233 AC: 35457 AN: 152316 Hom.: 4829 Cov.: 34 AF XY: 0.232 AC XY: 17243 AN XY: 74476

Gnomad4 AFR AF: 0.110

Gnomad4 AMR AF: 0.226

Gnomad4 ASJ AF: 0.323

Gnomad4 EAS AF: 0.511

Gnomad4 SAS AF: 0.273

Gnomad4 FIN AF: 0.234

Gnomad4 NFE AF: 0.278

Gnomad4 OTH AF: 0.243

Alfa AF: 0.276 Hom.: 13701

Bravo AF: 0.231

TwinsUK AF: 0.293 AC: 1086

ALSPAC AF: 0.291 AC: 1122

ESP6500AA AF: 0.116 AC: 510

ESP6500EA AF: 0.280 AC: 2411

ExAC AF: 0.275 AC: 33403

Asia WGS AF: 0.347 AC: 1203 AN: 3478

EpiCase AF: 0.283

EpiControl AF: 0.276

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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 42% of patients studied by a panel of primary immunodeficiencies. Number of patients: 40. Only high quality variants are reported. -

Immunodeficiency 35 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

This variant is associated with the following publications: (PMID: 26338038, 31961910, 19567624, 28973304, 26502338, 15657875) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.65
Cadd	Benign	7.3
Dann	Benign	0.84
DEOGEN2	Benign	0.067	T;T;T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.52	T;T;.;T
MetaRNN	Benign	0.00015	T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.0	L;.;L;.
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.52	N;N;N;N
REVEL	Benign	0.053
Sift	Benign	0.092	T;T;T;T
Sift4G	Uncertain	0.056	T;T;T;T
Polyphen		0.015	B;.;B;B
Vest4		0.077
MPC		0.37
ClinPred		0.0021	T
GERP RS		-0.83
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.056
gMVP		0.27

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.27		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.27		Position offset: -9

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

Publications

LitVar

Other links and lift over

dbSNP: rs2304256; hg19: chr19-10475652; COSMIC: COSV53384695; COSMIC: COSV53384695;