19-10359299-A-T

Variant names:

• chr19-10359299-A-T
• rs12720356
• NM_003331.5:c.2051T>A

Variant summary

Our verdict is Uncertain significance. The variant received 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 Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TYK2 NM_003331.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.08
• Publications: 0 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: Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

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

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TYK2	NM_003331.5	MANE Select	c.2051T>A	p.Ile684Asn	missense	Exon 15 of 25	NP_003322.3
	TYK2	NM_001385204.1		c.2051T>A	p.Ile684Asn	missense	Exon 15 of 25	NP_001372133.1
	TYK2	NM_001385203.1		c.2051T>A	p.Ile684Asn	missense	Exon 15 of 26	NP_001372132.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TYK2	ENST00000525621.6	TSL:1 MANE Select	c.2051T>A	p.Ile684Asn	missense	Exon 15 of 25	ENSP00000431885.1	P29597
	TYK2	ENST00000524462.5	TSL:1	c.1496T>A	p.Ile499Asn	missense	Exon 11 of 21	ENSP00000433203.1	E9PM19
	TYK2	ENST00000531836.7	TSL:4	c.2051T>A	p.Ile684Asn	missense	Exon 15 of 25	ENSP00000436175.2	P29597

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.67	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Uncertain	0.0082	D
MutationAssessor	Pathogenic	2.9	M
PhyloP100		7.1
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-6.1	D
REVEL	Uncertain	0.45
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.70
MutPred		0.59		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
Mutation Taster		=30/70	disease causing

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: rs12720356; hg19: chr19-10469975;