NM_003331.5:c.2017G>A

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_003331.5(TYK2):​c.2017G>A​(p.Val673Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000573 in 1,395,334 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 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. V673L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000057 (0 hom.)
• Consequence: TYK2 NM_003331.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2699227).

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>A	p.Val673Met	missense	Exon 14 of 25	NP_003322.3
	TYK2	NM_001385204.1		c.2017G>A	p.Val673Met	missense	Exon 14 of 25	NP_001372133.1
	TYK2	NM_001385203.1		c.2017G>A	p.Val673Met	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>A	p.Val673Met	missense	Exon 14 of 25	ENSP00000431885.1	P29597
	TYK2	ENST00000524462.5	TSL:1	c.1462G>A	p.Val488Met	missense	Exon 10 of 21	ENSP00000433203.1	E9PM19
	TYK2	ENST00000531836.7	TSL:4	c.2017G>A	p.Val673Met	missense	Exon 14 of 25	ENSP00000436175.2	P29597

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00 AC: 0 AN: 152456 AF XY: 0.00

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000573 AC: 8 AN: 1395334 Hom.: 0 Cov.: 33 AF XY: 0.0000102 AC XY: 7 AN XY: 688424

African (AFR) AF: 0.0000633 AC: 2 AN: 31600

American (AMR) AF: 0.00 AC: 0 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: 0.00000185 AC: 2 AN: 1078936

Other (OTH) AF: 0.0000345 AC: 2 AN: 57982

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Immunodeficiency 35 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.087	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.24	N
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-0.47	T
MutationAssessor	Benign	1.6	L
PhyloP100		0.0010
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.98	N
REVEL	Uncertain	0.31
Sift	Benign	0.10	T
Sift4G	Benign	0.090	T
Polyphen		0.97	D
Vest4		0.41
MutPred		0.64		Loss of stability (P = 0.072)
MVP		0.49
MPC		0.56
ClinPred		0.71	D
GERP RS		1.1
Varity_R		0.12
gMVP		0.59
Mutation Taster		=77/23	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;