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: Labcorp Genetics (formerly Invitae), Orphanet

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

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.-316G>A		5_prime_UTR	Exon 1 of 25	NP_003322.3
	TYK2	NM_001385204.1		c.-316G>A		5_prime_UTR	Exon 1 of 25	NP_001372133.1
	TYK2	NM_001385203.1		c.-316G>A		5_prime_UTR	Exon 1 of 26	NP_001372132.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TYK2	ENST00000524462.5	TSL:1	c.-91G>A		splice_region	Exon 1 of 21	ENSP00000433203.1	E9PM19
	TYK2	ENST00000525621.6	TSL:1 MANE Select	c.-316G>A		5_prime_UTR	Exon 1 of 25	ENSP00000431885.1	P29597
	TYK2	ENST00000524462.5	TSL:1	c.-91G>A		5_prime_UTR	Exon 1 of 21	ENSP00000433203.1	E9PM19

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Immunodeficiency 35 (1)
-	1	-	Virus-induced diabetes (1)

Computational scores

Source: dbNSFP v4.9

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;