rs12720355

Positions:

• chr19-10361776-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_003331.5(TYK2):​c.1953C>T​(p.Ile651=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0136 in 1,612,786 control chromosomes in the GnomAD database, including 179 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (17 hom., cov: 31)
  • Exomes 𝑓: 0.014 (162 hom.)
• Consequence: TYK2 NM_003331.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.44

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 19-10361776-G-A is Benign according to our data. Variant chr19-10361776-G-A is described in ClinVar as [Benign]. Clinvar id is 259042.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-10361776-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.44 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00999 (1514/151540) while in subpopulation NFE AF= 0.0159 (1077/67864). AF 95% confidence interval is 0.0151. There are 17 homozygotes in gnomad4. There are 730 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TYK2	NM_003331.5	c.1953C>T	p.Ile651=	synonymous_variant	13/25	ENST00000525621.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TYK2	ENST00000525621.6	c.1953C>T	p.Ile651=	synonymous_variant	13/25	1	NM_003331.5	P1

Frequencies

GnomAD3 genomes AF: 0.0100 AC: 1514 AN: 151418 Hom.: 17 Cov.: 31

Gnomad AFR AF: 0.00250

Gnomad AMI AF: 0.0287

Gnomad AMR AF: 0.00737

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.000195

Gnomad SAS AF: 0.00751

Gnomad FIN AF: 0.0125

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.0159

Gnomad OTH AF: 0.00719

GnomAD3 exomes AF: 0.00957 AC: 2398 AN: 250616 Hom.: 10 AF XY: 0.00984 AC XY: 1334 AN XY: 135576

Gnomad AFR exome AF: 0.00265

Gnomad AMR exome AF: 0.00492

Gnomad ASJ exome AF: 0.00427

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00666

Gnomad FIN exome AF: 0.0123

Gnomad NFE exome AF: 0.0142

Gnomad OTH exome AF: 0.0104

GnomAD4 exome AF: 0.0140 AC: 20398 AN: 1461246 Hom.: 162 Cov.: 36 AF XY: 0.0139 AC XY: 10091 AN XY: 726978

Gnomad4 AFR exome AF: 0.00221

Gnomad4 AMR exome AF: 0.00543

Gnomad4 ASJ exome AF: 0.00413

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00663

Gnomad4 FIN exome AF: 0.0118

Gnomad4 NFE exome AF: 0.0162

Gnomad4 OTH exome AF: 0.0116

GnomAD4 genome AF: 0.00999 AC: 1514 AN: 151540 Hom.: 17 Cov.: 31 AF XY: 0.00986 AC XY: 730 AN XY: 74058

Gnomad4 AFR AF: 0.00250

Gnomad4 AMR AF: 0.00736

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.000196

Gnomad4 SAS AF: 0.00751

Gnomad4 FIN AF: 0.0125

Gnomad4 NFE AF: 0.0159

Gnomad4 OTH AF: 0.00712

Alfa AF: 0.0133 Hom.: 20

Bravo AF: 0.00936

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.0145

EpiControl AF: 0.0132

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	TYK2: BP4, BP7, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Immunodeficiency 35 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	1.8
DANN	Benign	0.63

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: rs12720355; hg19: chr19-10472452; COSMIC: COSV53385701; COSMIC: COSV53385701;