chr19-10354054-A-T

Position:

• chr19-10354054-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_003331.5(TYK2):​c.2896T>A​(p.Cys966Ser) 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.

• 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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.98

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TYK2	NM_003331.5	c.2896T>A	p.Cys966Ser	missense_variant	20/25	ENST00000525621.6	NP_003322.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TYK2	ENST00000525621.6	c.2896T>A	p.Cys966Ser	missense_variant	20/25	1	NM_003331.5	ENSP00000431885.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Uncertain	0.47	T;D;T;.
Eigen	Benign	0.018
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.74	T;T;.;T
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Benign	1.3	L;.;L;.
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-7.4	D;D;D;.
REVEL	Pathogenic	0.67
Sift	Uncertain	0.027	D;D;D;.
Sift4G	Benign	0.070	T;T;T;D
Polyphen		0.41	B;.;B;.
Vest4		0.64
MutPred		0.90		Gain of disorder (P = 0.0042);.;Gain of disorder (P = 0.0042);.;
MVP		0.81
MPC		0.70
ClinPred		0.99	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.80
gMVP		0.69

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: rs763754692; hg19: chr19-10464730;