rs12720270

Positions:

• chr19-10365084-G-A
• chr19-10365084-G-C

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.1012-36C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.192 in 1,565,406 control chromosomes in the GnomAD database, including 31,415 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2637 hom., cov: 33)
  • Exomes 𝑓: 0.19 (28778 hom.)
• Consequence: TYK2 NM_003331.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0140

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=-0.87).
• BP6: Variant 19-10365084-G-A is Benign according to our data. Variant chr19-10365084-G-A is described in ClinVar as [Benign]. Clinvar id is 1257593.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.474 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TYK2	NM_003331.5	c.1012-36C>T		intron_variant		ENST00000525621.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TYK2	ENST00000525621.6	c.1012-36C>T		intron_variant		1	NM_003331.5	P1

Frequencies

GnomAD3 genomes AF: 0.165 AC: 25031 AN: 152132 Hom.: 2636 Cov.: 33

Gnomad AFR AF: 0.0654

Gnomad AMI AF: 0.366

Gnomad AMR AF: 0.166

Gnomad ASJ AF: 0.224

Gnomad EAS AF: 0.489

Gnomad SAS AF: 0.228

Gnomad FIN AF: 0.151

Gnomad MID AF: 0.187

Gnomad NFE AF: 0.191

Gnomad OTH AF: 0.174

GnomAD3 exomes AF: 0.209 AC: 42480 AN: 203320 Hom.: 5284 AF XY: 0.211 AC XY: 22981 AN XY: 108938

Gnomad AFR exome AF: 0.0629

Gnomad AMR exome AF: 0.163

Gnomad ASJ exome AF: 0.210

Gnomad EAS exome AF: 0.505

Gnomad SAS exome AF: 0.224

Gnomad FIN exome AF: 0.161

Gnomad NFE exome AF: 0.197

Gnomad OTH exome AF: 0.201

GnomAD4 exome AF: 0.194 AC: 274774 AN: 1413156 Hom.: 28778 Cov.: 32 AF XY: 0.195 AC XY: 136131 AN XY: 698046

Gnomad4 AFR exome AF: 0.0578

Gnomad4 AMR exome AF: 0.161

Gnomad4 ASJ exome AF: 0.205

Gnomad4 EAS exome AF: 0.422

Gnomad4 SAS exome AF: 0.216

Gnomad4 FIN exome AF: 0.165

Gnomad4 NFE exome AF: 0.191

Gnomad4 OTH exome AF: 0.204

GnomAD4 genome AF: 0.164 AC: 25043 AN: 152250 Hom.: 2637 Cov.: 33 AF XY: 0.165 AC XY: 12244 AN XY: 74426

Gnomad4 AFR AF: 0.0654

Gnomad4 AMR AF: 0.167

Gnomad4 ASJ AF: 0.224

Gnomad4 EAS AF: 0.490

Gnomad4 SAS AF: 0.229

Gnomad4 FIN AF: 0.151

Gnomad4 NFE AF: 0.191

Gnomad4 OTH AF: 0.173

Alfa AF: 0.163 Hom.: 491

Bravo AF: 0.164

Asia WGS AF: 0.316 AC: 1094 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Nov 12, 2023

This variant is classified as Benign based on local population frequency. This variant was detected in 31% of patients studied by a panel of primary immunodeficiencies. Number of patients: 30. Only high quality variants are reported. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 07, 2018

This variant is associated with the following publications: (PMID: 19567624, 31961910) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	2.2
DANN	Benign	0.44

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

Publications

LitVar

Other links and lift over

dbSNP: rs12720270; hg19: chr19-10475760; COSMIC: COSV53385751; COSMIC: COSV53385751;