rs35018800

chr19-10354167-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP3 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003331.5(TYK2):c.2783C>T(p.Ala928Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00635 in 1,613,810 control chromosomes in the GnomAD database, including 54 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0047 (8 hom., cov: 32)
  • Exomes 𝑓: 0.0065 (46 hom.)
• Consequence: TYK2 NM_003331.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 9.54

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 -19 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 9: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Dann, Eigen, M_CAP, phyloP100way_vertebrate, REVEL [when FATHMM_MKL, MetaRNN, MutationAssessor, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.015576899).
• BP6: Variant 19-10354167-G-A is Benign according to our data. Variant chr19-10354167-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 287098.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-10354167-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00474 (722/152300) while in subpopulation NFE AF= 0.00806 (548/68032). AF 95% confidence interval is 0.0075. There are 8 homozygotes in gnomad4. There are 313 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TYK2	NM_003331.5	c.2783C>T	p.Ala928Val	missense_variant	20/25	ENST00000525621.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TYK2	ENST00000525621.6	c.2783C>T	p.Ala928Val	missense_variant	20/25	1	NM_003331.5	P1

Frequencies

GnomAD3 genomes AF: 0.00474 AC: 722 AN: 152182 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.00145

Gnomad AMI AF: 0.0263

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00433

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00805

Gnomad OTH AF: 0.00573

GnomAD3 exomes AF: 0.00464 AC: 1164 AN: 250964 Hom.: 8 AF XY: 0.00458 AC XY: 621 AN XY: 135690

Gnomad AFR exome AF: 0.00111

Gnomad AMR exome AF: 0.00202

Gnomad ASJ exome AF: 0.00159

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000621

Gnomad FIN exome AF: 0.00499

Gnomad NFE exome AF: 0.00802

Gnomad OTH exome AF: 0.00391

GnomAD4 exome AF: 0.00651 AC: 9519 AN: 1461510 Hom.: 46 Cov.: 33 AF XY: 0.00638 AC XY: 4642 AN XY: 727068

Gnomad4 AFR exome AF: 0.000926

Gnomad4 AMR exome AF: 0.00190

Gnomad4 ASJ exome AF: 0.00226

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000661

Gnomad4 FIN exome AF: 0.00659

Gnomad4 NFE exome AF: 0.00782

Gnomad4 OTH exome AF: 0.00392

GnomAD4 genome AF: 0.00474 AC: 722 AN: 152300 Hom.: 8 Cov.: 32 AF XY: 0.00420 AC XY: 313 AN XY: 74468

Gnomad4 AFR AF: 0.00144

Gnomad4 AMR AF: 0.00144

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00433

Gnomad4 NFE AF: 0.00806

Gnomad4 OTH AF: 0.00567

Alfa AF: 0.00690 Hom.: 9

Bravo AF: 0.00453

TwinsUK AF: 0.00701 AC: 26

ALSPAC AF: 0.00960 AC: 37

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.00791 AC: 68

ExAC AF: 0.00510 AC: 619

EpiCase AF: 0.00671

EpiControl AF: 0.00646

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	TYK2: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 14, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 12, 2020	This variant is associated with the following publications: (PMID: 18270328, 25849893, 26338038, 17344846, 22543157, 30224649, 32707200) -

Immunodeficiency 35 Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Nov 10, 2017	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Apr 01, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Pathogenic	0.50
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.46	T;D;T;.
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.98	D;D;.;D
M_CAP	Pathogenic	0.33	D
MetaRNN	Benign	0.016	T;T;T;T
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Benign	1.9	L;.;L;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-3.7	D;D;D;.
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0010	D;D;D;.
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;.;D;.
Vest4		0.91
MVP		0.91
MPC		0.94
ClinPred		0.031	T
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.90
gMVP		0.80

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

Publications

LitVar

Other links and lift over

dbSNP: rs35018800; hg19: chr19-10464843; COSMIC: COSV53386305; COSMIC: COSV53386305;