NM_003331.5:c.-452G>A

Variant names:

• chr19-10380646-C-T
• rs280501
• NM_003331.5:c.-452G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003331.5(TYK2):​c.-452G>A variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.199 in 151,158 control chromosomes in the GnomAD database, including 3,549 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.20 (3549 hom., cov: 31)
  • Exomes 𝑓: 0.075 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TYK2 NM_003331.5 upstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.36
• Publications: 16 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: Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.323 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TYK2	NM_003331.5	MANE Select	c.-452G>A		upstream_gene	N/A	NP_003322.3
	TYK2	NM_001385204.1		c.-452G>A		upstream_gene	N/A	NP_001372133.1
	TYK2	NM_001385203.1		c.-452G>A		upstream_gene	N/A	NP_001372132.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TYK2	ENST00000525621.6	TSL:1 MANE Select	c.-452G>A		upstream_gene	N/A	ENSP00000431885.1
	TYK2	ENST00000524462.5	TSL:1	c.-227G>A		upstream_gene	N/A	ENSP00000433203.1
	TYK2	ENST00000531836.7	TSL:4	c.-362G>A		upstream_gene	N/A	ENSP00000436175.2

Frequencies

GnomAD3 genomes AF: 0.199 AC: 30043 AN: 151050 Hom.: 3533 Cov.: 31

Gnomad AFR AF: 0.327

Gnomad AMI AF: 0.0938

Gnomad AMR AF: 0.130

Gnomad ASJ AF: 0.166

Gnomad EAS AF: 0.0380

Gnomad SAS AF: 0.188

Gnomad FIN AF: 0.181

Gnomad MID AF: 0.242

Gnomad NFE AF: 0.155

Gnomad OTH AF: 0.184

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0747 AC: 13 AN: 174 Hom.: 0 Cov.: 0 AF XY: 0.0849 AC XY: 9 AN XY: 106

African (AFR) AF: 0.00 AC: 0 AN: 2

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.0847 AC: 10 AN: 118

South Asian (SAS) AF: 0.0500 AC: 1 AN: 20

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2

European-Non Finnish (NFE) AF: 0.0625 AC: 2 AN: 32

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.199 AC: 30102 AN: 151158 Hom.: 3549 Cov.: 31 AF XY: 0.197 AC XY: 14510 AN XY: 73770

African (AFR) AF: 0.328 AC: 13497 AN: 41190

American (AMR) AF: 0.130 AC: 1969 AN: 15184

Ashkenazi Jewish (ASJ) AF: 0.166 AC: 576 AN: 3470

East Asian (EAS) AF: 0.0379 AC: 191 AN: 5042

South Asian (SAS) AF: 0.188 AC: 894 AN: 4756

European-Finnish (FIN) AF: 0.181 AC: 1880 AN: 10380

Middle Eastern (MID) AF: 0.240 AC: 70 AN: 292

European-Non Finnish (NFE) AF: 0.155 AC: 10545 AN: 67832

Other (OTH) AF: 0.188 AC: 395 AN: 2106

Alfa AF: 0.166 Hom.: 7855

Bravo AF: 0.199

Asia WGS AF: 0.139 AC: 480 AN: 3470

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	1.2
DANN	Benign	0.68
PhyloP100		-1.4
PromoterAI		0.019	Neutral
Mutation Taster		=300/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs280501; hg19: chr19-10491322; COSMIC: COSV53385847; COSMIC: COSV53385847;