rs12720299

Positions:

• chr19-10357992-C-G

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.2311+11G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.137 in 1,613,420 control chromosomes in the GnomAD database, including 16,071 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1156 hom., cov: 33)
  • Exomes 𝑓: 0.14 (14915 hom.)
• Consequence: TYK2 NM_003331.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -2.35

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 19-10357992-C-G is Benign according to our data. Variant chr19-10357992-C-G is described in ClinVar as [Benign]. Clinvar id is 137868.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-10357992-C-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.143 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TYK2	NM_003331.5	c.2311+11G>C		intron_variant		ENST00000525621.6	NP_003322.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TYK2	ENST00000525621.6	c.2311+11G>C		intron_variant		1	NM_003331.5	ENSP00000431885	P1

Frequencies

GnomAD3 genomes AF: 0.118 AC: 17890 AN: 152170 Hom.: 1151 Cov.: 33

Gnomad AFR AF: 0.0842

Gnomad AMI AF: 0.152

Gnomad AMR AF: 0.0871

Gnomad ASJ AF: 0.116

Gnomad EAS AF: 0.0333

Gnomad SAS AF: 0.141

Gnomad FIN AF: 0.139

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.146

Gnomad OTH AF: 0.116

GnomAD3 exomes AF: 0.119 AC: 29716 AN: 249742 Hom.: 1996 AF XY: 0.123 AC XY: 16698 AN XY: 135450

Gnomad AFR exome AF: 0.0823

Gnomad AMR exome AF: 0.0631

Gnomad ASJ exome AF: 0.113

Gnomad EAS exome AF: 0.0302

Gnomad SAS exome AF: 0.150

Gnomad FIN exome AF: 0.142

Gnomad NFE exome AF: 0.143

Gnomad OTH exome AF: 0.126

GnomAD4 exome AF: 0.139 AC: 203118 AN: 1461132 Hom.: 14915 Cov.: 33 AF XY: 0.140 AC XY: 101483 AN XY: 726872

Gnomad4 AFR exome AF: 0.0827

Gnomad4 AMR exome AF: 0.0669

Gnomad4 ASJ exome AF: 0.111

Gnomad4 EAS exome AF: 0.0244

Gnomad4 SAS exome AF: 0.150

Gnomad4 FIN exome AF: 0.142

Gnomad4 NFE exome AF: 0.148

Gnomad4 OTH exome AF: 0.133

GnomAD4 genome AF: 0.118 AC: 17912 AN: 152288 Hom.: 1156 Cov.: 33 AF XY: 0.116 AC XY: 8635 AN XY: 74456

Gnomad4 AFR AF: 0.0844

Gnomad4 AMR AF: 0.0871

Gnomad4 ASJ AF: 0.116

Gnomad4 EAS AF: 0.0326

Gnomad4 SAS AF: 0.140

Gnomad4 FIN AF: 0.139

Gnomad4 NFE AF: 0.146

Gnomad4 OTH AF: 0.121

Alfa AF: 0.129 Hom.: 266

Bravo AF: 0.113

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 27, 2013	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. -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jan 24, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 20% of patients studied by a panel of primary immunodeficiencies. Number of patients: 19. Only high quality variants are reported. -

Immunodeficiency 35 Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.031
DANN	Benign	0.35

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: rs12720299; hg19: chr19-10468668;