rs34536443

chr19-10352442-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003331.5(TYK2):c.3310C>G(p.Pro1104Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0371 in 1,607,098 control chromosomes in the GnomAD database, including 1,233 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.028 (69 hom., cov: 32)
  • Exomes 𝑓: 0.038 (1164 hom.)
• Consequence: TYK2 NM_003331.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:6
• Conservation: PhyloP100: 7.51

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 (MetaRNN=0.009062827).
• BP6: Variant 19-10352442-G-C is Benign according to our data. Variant chr19-10352442-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 137869.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-10352442-G-C is described in Lovd as [Likely_benign]. Variant chr19-10352442-G-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0278 (4238/152278) while in subpopulation NFE AF= 0.044 (2990/68018). AF 95% confidence interval is 0.0426. There are 69 homozygotes in gnomad4. There are 1983 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 69 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TYK2	NM_003331.5	c.3310C>G	p.Pro1104Ala	missense_variant	23/25	ENST00000525621.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TYK2	ENST00000525621.6	c.3310C>G	p.Pro1104Ala	missense_variant	23/25	1	NM_003331.5	P1

Frequencies

GnomAD3 genomes AF: 0.0278 AC: 4235 AN: 152160 Hom.: 69 Cov.: 32

Gnomad AFR AF: 0.00914

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.0214

Gnomad ASJ AF: 0.0332

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0114

Gnomad FIN AF: 0.0287

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0439

Gnomad OTH AF: 0.0206

GnomAD3 exomes AF: 0.0268 AC: 6632 AN: 247438 Hom.: 123 AF XY: 0.0271 AC XY: 3628 AN XY: 133876

Gnomad AFR exome AF: 0.00712

Gnomad AMR exome AF: 0.0120

Gnomad ASJ exome AF: 0.0301

Gnomad EAS exome AF: 0.0000551

Gnomad SAS exome AF: 0.0111

Gnomad FIN exome AF: 0.0311

Gnomad NFE exome AF: 0.0417

Gnomad OTH exome AF: 0.0251

GnomAD4 exome AF: 0.0381 AC: 55360 AN: 1454820 Hom.: 1164 Cov.: 30 AF XY: 0.0371 AC XY: 26862 AN XY: 723964

Gnomad4 AFR exome AF: 0.00703

Gnomad4 AMR exome AF: 0.0123

Gnomad4 ASJ exome AF: 0.0305

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0115

Gnomad4 FIN exome AF: 0.0300

Gnomad4 NFE exome AF: 0.0445

Gnomad4 OTH exome AF: 0.0299

GnomAD4 genome AF: 0.0278 AC: 4238 AN: 152278 Hom.: 69 Cov.: 32 AF XY: 0.0266 AC XY: 1983 AN XY: 74448

Gnomad4 AFR AF: 0.00912

Gnomad4 AMR AF: 0.0214

Gnomad4 ASJ AF: 0.0332

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0118

Gnomad4 FIN AF: 0.0287

Gnomad4 NFE AF: 0.0440

Gnomad4 OTH AF: 0.0204

Alfa AF: 0.0382 Hom.: 91

Bravo AF: 0.0262

TwinsUK AF: 0.0475 AC: 176

ALSPAC AF: 0.0527 AC: 203

ESP6500AA AF: 0.00681 AC: 30

ESP6500EA AF: 0.0403 AC: 347

ExAC AF: 0.0268 AC: 3256

Asia WGS AF: 0.00635 AC: 22 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1 Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Immunodeficiency 35 Pathogenic:1 Benign:2

Likely 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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 26, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 28, 2014	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, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:1

Likely benign, no assertion criteria provided

clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Uncertain	-0.070
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T;D;T
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	D;D;.
MetaRNN	Benign	0.0091	T;T;T
MetaSVM	Uncertain	-0.060	T
MutationAssessor	Benign	1.4	L;.;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-6.8	D;D;D
REVEL	Uncertain	0.59
Sift	Uncertain	0.0020	D;D;D
Sift4G	Uncertain	0.0070	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.22
MPC		0.81
ClinPred		0.028	T
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.68
gMVP		0.67

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: rs34536443; hg19: chr19-10463118;