NM_003331.5:c.2051T>A

Variant names:

• chr19-10359299-A-T
• NM_003331.5:c.2051T>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_003331.5(TYK2):​c.2051T>A​(p.Ile684Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 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. I684S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TYK2 NM_003331.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.08

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.888

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TYK2	NM_003331.5	c.2051T>A	p.Ile684Asn	missense_variant	Exon 15 of 25	ENST00000525621.6	NP_003322.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TYK2	ENST00000525621.6	c.2051T>A	p.Ile684Asn	missense_variant	Exon 15 of 25	1	NM_003331.5	ENSP00000431885.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.49	T;D;T;.
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;.;D
M_CAP	Pathogenic	0.67	D
MetaRNN	Pathogenic	0.89	D;D;D;D
MetaSVM	Uncertain	0.0082	D
MutationAssessor	Pathogenic	2.9	M;.;M;.
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-6.1	D;D;D;D
REVEL	Uncertain	0.45
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D
Polyphen		1.0	D;.;D;D
Vest4		0.70
MutPred		0.59		Gain of disorder (P = 0.0188);.;Gain of disorder (P = 0.0188);Gain of disorder (P = 0.0188);
MVP		0.81
MPC		1.2
ClinPred		1.0	D
GERP RS		3.7
Varity_R		0.90
gMVP		0.86

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-10469975;