rs2304255

Variant names:

• chr19-10364973-C-T
• rs2304255
• NM_003331.5:c.1087G>A

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.1087G>A​(p.Gly363Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0703 in 1,613,992 control chromosomes in the GnomAD database, including 4,365 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.055 (295 hom., cov: 33)
  • Exomes 𝑓: 0.072 (4070 hom.)
• Consequence: TYK2 NM_003331.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.30
• Publications: 39 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 (MetaRNN=0.002353698).
• BP6: Variant 19-10364973-C-T is Benign according to our data. Variant chr19-10364973-C-T is described in ClinVar as Benign. ClinVar VariationId is 137864.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0765 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TYK2	NM_003331.5	c.1087G>A	p.Gly363Ser	missense_variant	Exon 8 of 25	ENST00000525621.6	NP_003322.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TYK2	ENST00000525621.6	c.1087G>A	p.Gly363Ser	missense_variant	Exon 8 of 25	1	NM_003331.5	ENSP00000431885.1

Frequencies

GnomAD3 genomes AF: 0.0550 AC: 8378 AN: 152256 Hom.: 291 Cov.: 33

Gnomad AFR AF: 0.0157

Gnomad AMI AF: 0.0789

Gnomad AMR AF: 0.0463

Gnomad ASJ AF: 0.0724

Gnomad EAS AF: 0.0250

Gnomad SAS AF: 0.0775

Gnomad FIN AF: 0.0688

Gnomad MID AF: 0.0764

Gnomad NFE AF: 0.0782

Gnomad OTH AF: 0.0550

GnomAD2 exomes AF: 0.0622 AC: 15602 AN: 250708 AF XY: 0.0647

Gnomad AFR exome AF: 0.0154

Gnomad AMR exome AF: 0.0312

Gnomad ASJ exome AF: 0.0729

Gnomad EAS exome AF: 0.0239

Gnomad FIN exome AF: 0.0670

Gnomad NFE exome AF: 0.0768

Gnomad OTH exome AF: 0.0711

GnomAD4 exome AF: 0.0719 AC: 105111 AN: 1461618 Hom.: 4070 Cov.: 33 AF XY: 0.0727 AC XY: 52865 AN XY: 727128

African (AFR) AF: 0.0146 AC: 488 AN: 33480

American (AMR) AF: 0.0334 AC: 1493 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0699 AC: 1827 AN: 26134

East Asian (EAS) AF: 0.0156 AC: 619 AN: 39696

South Asian (SAS) AF: 0.0813 AC: 7014 AN: 86256

European-Finnish (FIN) AF: 0.0671 AC: 3570 AN: 53220

Middle Eastern (MID) AF: 0.0631 AC: 364 AN: 5766

European-Non Finnish (NFE) AF: 0.0769 AC: 85555 AN: 1111962

Other (OTH) AF: 0.0692 AC: 4181 AN: 60388

GnomAD4 genome AF: 0.0551 AC: 8399 AN: 152374 Hom.: 295 Cov.: 33 AF XY: 0.0547 AC XY: 4079 AN XY: 74514

African (AFR) AF: 0.0159 AC: 663 AN: 41592

American (AMR) AF: 0.0463 AC: 709 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0724 AC: 251 AN: 3468

East Asian (EAS) AF: 0.0248 AC: 129 AN: 5192

South Asian (SAS) AF: 0.0774 AC: 374 AN: 4834

European-Finnish (FIN) AF: 0.0688 AC: 731 AN: 10628

Middle Eastern (MID) AF: 0.0753 AC: 22 AN: 292

European-Non Finnish (NFE) AF: 0.0782 AC: 5322 AN: 68034

Other (OTH) AF: 0.0596 AC: 126 AN: 2114

Alfa AF: 0.0658 Hom.: 174

Bravo AF: 0.0516

TwinsUK AF: 0.0782 AC: 290

ALSPAC AF: 0.0789 AC: 304

ESP6500AA AF: 0.0175 AC: 77

ESP6500EA AF: 0.0784 AC: 674

ExAC AF: 0.0636 AC: 7724

Asia WGS AF: 0.0610 AC: 213 AN: 3478

EpiCase AF: 0.0771

EpiControl AF: 0.0738

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Immunodeficiency 35 Benign:3

Mar 06, 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. -

May 18, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:2

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 06, 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
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.029
DANN	Benign	0.58
DEOGEN2	Benign	0.051	T;T;T;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.036	N
LIST_S2	Benign	0.21	T;T;.;T
MetaRNN	Benign	0.0024	T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.67	N;.;N;.
PhyloP100		-1.3
PrimateAI	Benign	0.22	T
PROVEAN	Benign	0.53	N;N;N;N
REVEL	Benign	0.027
Sift	Benign	0.48	T;T;T;T
Sift4G	Benign	0.71	T;T;T;T
Polyphen		0.0020	B;.;B;B
Vest4		0.047
MPC		0.26
ClinPred		0.0015	T
GERP RS		-6.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.040
gMVP		0.13
Mutation Taster		=93/7	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: rs2304255; hg19: chr19-10475649; COSMIC: COSV53384815; COSMIC: COSV53384815;