19-10361541-C-A

Variant names:

• chr19-10361541-C-A
• rs528691386
• NM_003331.5:c.2017G>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_003331.5(TYK2):​c.2017G>T​(p.Val673Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000147 in 1,547,262 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V673M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: TYK2 NM_003331.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 0.00100
• Publications: 2 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.04473111).

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.2017G>T	p.Val673Leu	missense	Exon 14 of 25	NP_003322.3
	TYK2	NM_001385204.1		c.2017G>T	p.Val673Leu	missense	Exon 14 of 25	NP_001372133.1
	TYK2	NM_001385203.1		c.2017G>T	p.Val673Leu	missense	Exon 14 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.2017G>T	p.Val673Leu	missense	Exon 14 of 25	ENSP00000431885.1	P29597
	TYK2	ENST00000524462.5	TSL:1	c.1462G>T	p.Val488Leu	missense	Exon 10 of 21	ENSP00000433203.1	E9PM19
	TYK2	ENST00000531836.7	TSL:4	c.2017G>T	p.Val673Leu	missense	Exon 14 of 25	ENSP00000436175.2	P29597

Frequencies

GnomAD3 genomes AF: 0.000191 AC: 29 AN: 151930 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000986

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000177

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000722 AC: 11 AN: 152456 AF XY: 0.0000620

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000808

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000133

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000143 AC: 199 AN: 1395332 Hom.: 0 Cov.: 33 AF XY: 0.000137 AC XY: 94 AN XY: 688424

African (AFR) AF: 0.00 AC: 0 AN: 31600

American (AMR) AF: 0.0000840 AC: 3 AN: 35696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25176

East Asian (EAS) AF: 0.00 AC: 0 AN: 35824

South Asian (SAS) AF: 0.0000252 AC: 2 AN: 79240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45212

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5668

European-Non Finnish (NFE) AF: 0.000175 AC: 189 AN: 1078936

Other (OTH) AF: 0.0000862 AC: 5 AN: 57980

GnomAD4 genome AF: 0.000191 AC: 29 AN: 151930 Hom.: 0 Cov.: 31 AF XY: 0.000216 AC XY: 16 AN XY: 74204

African (AFR) AF: 0.0000242 AC: 1 AN: 41358

American (AMR) AF: 0.000986 AC: 15 AN: 15212

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000177 AC: 12 AN: 67958

Other (OTH) AF: 0.000478 AC: 1 AN: 2090

Alfa AF: 0.000138 Hom.: 0

Bravo AF: 0.000140

ExAC AF: 0.0000280 AC: 2

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Immunodeficiency 35 (2)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	11
DANN	Benign	0.93
DEOGEN2	Benign	0.16	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.045	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.53	N
PhyloP100		0.0010
PrimateAI	Uncertain	0.48	T
PROVEAN	Benign	-0.41	N
REVEL	Benign	0.12
Sift	Benign	0.67	T
Sift4G	Benign	0.50	T
Polyphen		0.0050	B
Vest4		0.33
MutPred		0.63		Loss of sheet (P = 0.1398)
MVP		0.22
MPC		0.32
ClinPred		0.040	T
GERP RS		1.1
Varity_R		0.11
gMVP		0.52
Mutation Taster		=83/17	polymorphism

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: rs528691386; hg19: chr19-10472217;