rs55882956

chr19-10359243-G-Achr19-10359243-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003331.5(TYK2):c.2107C>T(p.Arg703Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00298 in 1,610,784 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R703Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0028 (4 hom., cov: 31)
  • Exomes 𝑓: 0.0030 (36 hom.)
• Consequence: TYK2 NM_003331.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.13

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=0.006138116).
• BP6: Variant 19-10359243-G-A is Benign according to our data. Variant chr19-10359243-G-A is described in ClinVar as [Benign]. Clinvar id is 327942.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-10359243-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00283 (431/152282) while in subpopulation EAS AF= 0.0261 (135/5172). AF 95% confidence interval is 0.0225. There are 4 homozygotes in gnomad4. There are 210 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TYK2	NM_003331.5	c.2107C>T	p.Arg703Trp	missense_variant	15/25	ENST00000525621.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TYK2	ENST00000525621.6	c.2107C>T	p.Arg703Trp	missense_variant	15/25	1	NM_003331.5	P1

Frequencies

GnomAD3 genomes AF: 0.00286 AC: 435 AN: 152164 Hom.: 4 Cov.: 31

Gnomad AFR AF: 0.000603

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0100

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.0264

Gnomad SAS AF: 0.00373

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00135

Gnomad OTH AF: 0.00383

GnomAD3 exomes AF: 0.00721 AC: 1779 AN: 246894 Hom.: 17 AF XY: 0.00609 AC XY: 817 AN XY: 134206

Gnomad AFR exome AF: 0.000502

Gnomad AMR exome AF: 0.0283

Gnomad ASJ exome AF: 0.000801

Gnomad EAS exome AF: 0.0301

Gnomad SAS exome AF: 0.00259

Gnomad FIN exome AF: 0.0000507

Gnomad NFE exome AF: 0.00116

Gnomad OTH exome AF: 0.00495

GnomAD4 exome AF: 0.00300 AC: 4372 AN: 1458502 Hom.: 36 Cov.: 32 AF XY: 0.00291 AC XY: 2112 AN XY: 725646

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.0254

Gnomad4 ASJ exome AF: 0.000727

Gnomad4 EAS exome AF: 0.0270

Gnomad4 SAS exome AF: 0.00269

Gnomad4 FIN exome AF: 0.0000991

Gnomad4 NFE exome AF: 0.00154

Gnomad4 OTH exome AF: 0.00305

GnomAD4 genome AF: 0.00283 AC: 431 AN: 152282 Hom.: 4 Cov.: 31 AF XY: 0.00282 AC XY: 210 AN XY: 74452

Gnomad4 AFR AF: 0.000601

Gnomad4 AMR AF: 0.00994

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.0261

Gnomad4 SAS AF: 0.00353

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00135

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.00167 Hom.: 2

Bravo AF: 0.00446

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00174 AC: 15

ExAC AF: 0.00664 AC: 806

Asia WGS AF: 0.0120 AC: 40 AN: 3478

EpiCase AF: 0.000927

EpiControl AF: 0.00119

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Immunodeficiency 35 Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

This variant is associated with the following publications: (PMID: 31118190, 28842327) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.21
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.63	D;D;D;.
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.44	N
LIST_S2	Uncertain	0.93	D;D;.;D
MetaRNN	Benign	0.0061	T;T;T;T
MetaSVM	Benign	-0.45	T
MutationAssessor	Pathogenic	2.9	M;.;M;.
MutationTaster	Benign	0.96	D;D;D;D
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-4.0	D;D;D;D
REVEL	Benign	0.21
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D
Polyphen		1.0	D;.;D;D
Vest4		0.44
MVP		0.53
MPC		0.90
ClinPred		0.036	T
GERP RS		0.034
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
Varity_R		0.32
gMVP		0.57

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs55882956; hg19: chr19-10469919;