rs280523

Variant names:

• chr19-10366530-G-A
• rs280523
• ENST00000524462.5:c.-40C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-10366530-G-A
• chr19-10366530-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000524462.5(TYK2):​c.-40C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0763 in 1,613,758 control chromosomes in the GnomAD database, including 5,295 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.098 (905 hom., cov: 31)
  • Exomes 𝑓: 0.074 (4390 hom.)
• Consequence: TYK2 ENST00000524462.5 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -4.51
• Publications: 35 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 19-10366530-G-A is Benign according to our data. Variant chr19-10366530-G-A is described in ClinVar as Benign. ClinVar VariationId is 137863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.172 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000524462.5. 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.516C>T	p.Thr172Thr	synonymous	Exon 6 of 25	NP_003322.3
	TYK2	NM_001385204.1		c.516C>T	p.Thr172Thr	synonymous	Exon 6 of 25	NP_001372133.1
	TYK2	NM_001385203.1		c.516C>T	p.Thr172Thr	synonymous	Exon 6 of 26	NP_001372132.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TYK2	ENST00000524462.5	TSL:1	c.-40C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 21	ENSP00000433203.1	E9PM19
	TYK2	ENST00000525621.6	TSL:1 MANE Select	c.516C>T	p.Thr172Thr	synonymous	Exon 6 of 25	ENSP00000431885.1	P29597
	TYK2	ENST00000524462.5	TSL:1	c.-40C>T		5_prime_UTR	Exon 2 of 21	ENSP00000433203.1	E9PM19

Frequencies

GnomAD3 genomes AF: 0.0983 AC: 14920 AN: 151796 Hom.: 902 Cov.: 31

Gnomad AFR AF: 0.175

Gnomad AMI AF: 0.0736

Gnomad AMR AF: 0.0564

Gnomad ASJ AF: 0.0452

Gnomad EAS AF: 0.0320

Gnomad SAS AF: 0.0635

Gnomad FIN AF: 0.116

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0695

Gnomad OTH AF: 0.0841

GnomAD2 exomes AF: 0.0721 AC: 18141 AN: 251476 AF XY: 0.0716

Gnomad AFR exome AF: 0.180

Gnomad AMR exome AF: 0.0398

Gnomad ASJ exome AF: 0.0422

Gnomad EAS exome AF: 0.0309

Gnomad FIN exome AF: 0.118

Gnomad NFE exome AF: 0.0691

Gnomad OTH exome AF: 0.0645

GnomAD4 exome AF: 0.0740 AC: 108115 AN: 1461844 Hom.: 4390 Cov.: 34 AF XY: 0.0732 AC XY: 53217 AN XY: 727228

African (AFR) AF: 0.181 AC: 6048 AN: 33478

American (AMR) AF: 0.0415 AC: 1858 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0436 AC: 1140 AN: 26136

East Asian (EAS) AF: 0.0458 AC: 1817 AN: 39698

South Asian (SAS) AF: 0.0681 AC: 5872 AN: 86256

European-Finnish (FIN) AF: 0.114 AC: 6114 AN: 53410

Middle Eastern (MID) AF: 0.0544 AC: 314 AN: 5768

European-Non Finnish (NFE) AF: 0.0724 AC: 80490 AN: 1111982

Other (OTH) AF: 0.0739 AC: 4462 AN: 60392

GnomAD4 genome AF: 0.0984 AC: 14942 AN: 151914 Hom.: 905 Cov.: 31 AF XY: 0.0986 AC XY: 7318 AN XY: 74248

African (AFR) AF: 0.175 AC: 7259 AN: 41432

American (AMR) AF: 0.0563 AC: 857 AN: 15222

Ashkenazi Jewish (ASJ) AF: 0.0452 AC: 157 AN: 3470

East Asian (EAS) AF: 0.0319 AC: 165 AN: 5174

South Asian (SAS) AF: 0.0626 AC: 301 AN: 4812

European-Finnish (FIN) AF: 0.116 AC: 1223 AN: 10546

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0695 AC: 4724 AN: 67950

Other (OTH) AF: 0.0837 AC: 176 AN: 2104

Alfa AF: 0.0790 Hom.: 978

Bravo AF: 0.0982

Asia WGS AF: 0.0680 AC: 237 AN: 3478

EpiCase AF: 0.0677

EpiControl AF: 0.0695

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.46
DANN	Benign	0.48
PhyloP100		-4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=95/5	polymorphism (auto)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs280523;

hg19: chr19-10477206;

COSMIC: COSV53385553;

COSMIC: COSV53385553;