ENST00000524462.5:c.-91G>A

Variant names:

• chr19-10380510-C-T
• rs2304258
• ENST00000524462.5:c.-91G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BS1 BS2

The ENST00000524462.5(TYK2):​c.-91G>A variant causes a splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00524 in 152,350 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0052 (14 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TYK2 ENST00000524462.5 splice_region
• Scores: Splicing: ADA: 0.1608
• Clinical Significance: Benign criteria provided, single submitter U:1 B:1
• Conservation: PhyloP100: 0.938
• Publications: 6 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=-0.43).
• BP6: Variant 19-10380510-C-T is Benign according to our data. Variant chr19-10380510-C-T is described in ClinVar as Benign. ClinVar VariationId is 440729.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00524 (798/152350) while in subpopulation EAS AF = 0.0315 (163/5178). AF 95% confidence interval is 0.0275. There are 14 homozygotes in GnomAd4. There are 539 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TYK2	NM_003331.5	c.-316G>A		5_prime_UTR_variant	Exon 1 of 25	ENST00000525621.6	NP_003322.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TYK2	ENST00000525621.6	c.-316G>A		5_prime_UTR_variant	Exon 1 of 25	1	NM_003331.5	ENSP00000431885.1

Frequencies

GnomAD3 genomes AF: 0.00526 AC: 800 AN: 152232 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.0318

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.0441

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00156

Gnomad OTH AF: 0.00478

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 234 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 148

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.00 AC: 0 AN: 142

South Asian (SAS) AF: 0.00 AC: 0 AN: 42

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 44

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.00524 AC: 798 AN: 152350 Hom.: 14 Cov.: 32 AF XY: 0.00724 AC XY: 539 AN XY: 74498

African (AFR) AF: 0.000361 AC: 15 AN: 41590

American (AMR) AF: 0.00163 AC: 25 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.0315 AC: 163 AN: 5178

South Asian (SAS) AF: 0.00207 AC: 10 AN: 4834

European-Finnish (FIN) AF: 0.0441 AC: 468 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00156 AC: 106 AN: 68036

Other (OTH) AF: 0.00473 AC: 10 AN: 2116

Alfa AF: 0.00339 Hom.: 0

Bravo AF: 0.00204

Asia WGS AF: 0.0290 AC: 101 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Virus-induced diabetes Uncertain:1

-

Division of Host Defense, Kyushu University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: reference population

- -

Immunodeficiency 35 Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	19
DANN	Benign	0.88
PhyloP100		0.94
PromoterAI		-0.078	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=298/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.16
dbscSNV1_RF	Benign	0.39

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

Other links and lift over

dbSNP: rs2304258; hg19: chr19-10491186;