Genetic Variant TYK2:p.Arg638Gly (chr19-10361817-G-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_003331.5(TYK2):c.1912C>G(p.Arg638Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R638L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

TYK2
NM_003331.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.06

Publications

7 publications found

Variant links:

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)

TYK2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003331.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TYK2	NM_003331.5	MANE Select	c.1912C>G	p.Arg638Gly	missense	Exon 13 of 25	NP_003322.3
TYK2	NM_001385204.1		c.1912C>G	p.Arg638Gly	missense	Exon 13 of 25	NP_001372133.1
TYK2	NM_001385203.1		c.1912C>G	p.Arg638Gly	missense	Exon 13 of 26	NP_001372132.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TYK2	ENST00000525621.6	TSL:1 MANE Select	c.1912C>G	p.Arg638Gly	missense	Exon 13 of 25	ENSP00000431885.1
TYK2	ENST00000524462.5	TSL:1	c.1357C>G	p.Arg453Gly	missense	Exon 9 of 21	ENSP00000433203.1
TYK2	ENST00000531836.7	TSL:4	c.1912C>G	p.Arg638Gly	missense	Exon 13 of 25	ENSP00000436175.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251124

AF XY:

0.00000736

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Uncertain

0.059

BayesDel_noAF

Benign

-0.15

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.52

Eigen

Benign

0.058

Eigen_PC

Benign

-0.14

FATHMM_MKL

Benign

0.40

LIST_S2

Uncertain

0.88

M_CAP

Pathogenic

0.32

MetaRNN

Uncertain

0.62

MetaSVM

Uncertain

-0.11

MutationAssessor

Uncertain

2.0

PhyloP100

1.1

PrimateAI

Benign

0.39

PROVEAN

Uncertain

-3.3

REVEL

Uncertain

0.44

Sift

Uncertain

0.0080

Sift4G

Benign

0.068

Polyphen

0.98

Vest4

0.65

MutPred

0.61

Loss of stability (P = 0.0979)

MVP

0.78

MPC

0.89

ClinPred

0.85

GERP RS

3.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.62

gMVP

0.81

Mutation Taster

=63/37

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over