rs280500

Positions:

• chr19-10379726-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003331.5(TYK2):​c.-132T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.192 in 152,152 control chromosomes in the GnomAD database, including 3,251 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (3251 hom., cov: 31)
  • Exomes 𝑓: 0.12 (0 hom.)
• Consequence: TYK2 NM_003331.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.256

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 19-10379726-A-G is Benign according to our data. Variant chr19-10379726-A-G is described in ClinVar as [Benign]. Clinvar id is 327965.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.296 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TYK2	NM_003331.5	c.-132T>C		5_prime_UTR_variant	2/25	ENST00000525621.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TYK2	ENST00000525621.6	c.-132T>C		5_prime_UTR_variant	2/25	1	NM_003331.5	P1

Frequencies

GnomAD3 genomes AF: 0.191 AC: 29078 AN: 151904 Hom.: 3240 Cov.: 31

Gnomad AFR AF: 0.300

Gnomad AMI AF: 0.0932

Gnomad AMR AF: 0.127

Gnomad ASJ AF: 0.166

Gnomad EAS AF: 0.0346

Gnomad SAS AF: 0.191

Gnomad FIN AF: 0.186

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.155

Gnomad OTH AF: 0.175

GnomAD4 exome AF: 0.115 AC: 15 AN: 130 Hom.: 0 Cov.: 0 AF XY: 0.143 AC XY: 10 AN XY: 70

Gnomad4 EAS exome AF: 0.0984

Gnomad4 FIN exome AF: 0.333

Gnomad4 NFE exome AF: 0.500

GnomAD4 genome AF: 0.192 AC: 29134 AN: 152022 Hom.: 3251 Cov.: 31 AF XY: 0.190 AC XY: 14081 AN XY: 74286

Gnomad4 AFR AF: 0.301

Gnomad4 AMR AF: 0.127

Gnomad4 ASJ AF: 0.166

Gnomad4 EAS AF: 0.0345

Gnomad4 SAS AF: 0.191

Gnomad4 FIN AF: 0.186

Gnomad4 NFE AF: 0.155

Gnomad4 OTH AF: 0.179

Alfa AF: 0.161 Hom.: 2912

Bravo AF: 0.190

Asia WGS AF: 0.143 AC: 494 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Immunodeficiency 35 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	9.4
DANN	Benign	0.74

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs280500; hg19: chr19-10490402;