rs12720222

Positions:

• chr19-10378495-C-T

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.-20-69G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.08 in 1,304,520 control chromosomes in the GnomAD database, including 4,598 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.098 (900 hom., cov: 32)
  • Exomes 𝑓: 0.078 (3698 hom.)
• Consequence: TYK2 NM_003331.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.643

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=-0.9).
• BP6: Variant 19-10378495-C-T is Benign according to our data. Variant chr19-10378495-C-T is described in ClinVar as [Benign]. Clinvar id is 676029.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.161 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TYK2	NM_003331.5	c.-20-69G>A		intron_variant		ENST00000525621.6	NP_003322.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TYK2	ENST00000525621.6	c.-20-69G>A		intron_variant		1	NM_003331.5	ENSP00000431885	P1

Frequencies

GnomAD3 genomes AF: 0.0978 AC: 14875 AN: 152136 Hom.: 893 Cov.: 32

Gnomad AFR AF: 0.164

Gnomad AMI AF: 0.0735

Gnomad AMR AF: 0.0568

Gnomad ASJ AF: 0.0615

Gnomad EAS AF: 0.0330

Gnomad SAS AF: 0.0645

Gnomad FIN AF: 0.118

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0737

Gnomad OTH AF: 0.0856

GnomAD4 exome AF: 0.0776 AC: 89469 AN: 1152266 Hom.: 3698 Cov.: 15 AF XY: 0.0768 AC XY: 44544 AN XY: 580134

Gnomad4 AFR exome AF: 0.171

Gnomad4 AMR exome AF: 0.0448

Gnomad4 ASJ exome AF: 0.0610

Gnomad4 EAS exome AF: 0.0467

Gnomad4 SAS exome AF: 0.0702

Gnomad4 FIN exome AF: 0.113

Gnomad4 NFE exome AF: 0.0770

Gnomad4 OTH exome AF: 0.0786

GnomAD4 genome AF: 0.0979 AC: 14906 AN: 152254 Hom.: 900 Cov.: 32 AF XY: 0.0978 AC XY: 7278 AN XY: 74440

Gnomad4 AFR AF: 0.164

Gnomad4 AMR AF: 0.0567

Gnomad4 ASJ AF: 0.0615

Gnomad4 EAS AF: 0.0327

Gnomad4 SAS AF: 0.0637

Gnomad4 FIN AF: 0.118

Gnomad4 NFE AF: 0.0737

Gnomad4 OTH AF: 0.0852

Alfa AF: 0.0883 Hom.: 97

Bravo AF: 0.0980

Asia WGS AF: 0.0730 AC: 253 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 19, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.1
DANN	Benign	0.51
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs12720222; hg19: chr19-10489171;