rs35018800

Variant names:

• chr19-10354167-G-A
• rs35018800
• NM_003331.5:c.2783C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP3 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003331.5(TYK2):​c.2783C>T​(p.Ala928Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00635 in 1,613,810 control chromosomes in the GnomAD database, including 54 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0047 (8 hom., cov: 32)
  • Exomes 𝑓: 0.0065 (46 hom.)
• Consequence: TYK2 NM_003331.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 9.54
• Publications: 53 publications found

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]

TYK2 Gene-Disease associations (from GenCC):

• immunodeficiency 35

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 10: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Dann, Eigen, M_CAP, phyloP100way_vertebrate, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationAssessor, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.015576899).
• BP6: Variant 19-10354167-G-A is Benign according to our data. Variant chr19-10354167-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 287098.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00474 (722/152300) while in subpopulation NFE AF = 0.00806 (548/68032). AF 95% confidence interval is 0.0075. There are 8 homozygotes in GnomAd4. There are 313 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003331.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TYK2	NM_003331.5	MANE Select	c.2783C>T	p.Ala928Val	missense	Exon 20 of 25	NP_003322.3
	TYK2	NM_001385204.1		c.2993C>T	p.Ala998Val	missense	Exon 20 of 25	NP_001372133.1
	TYK2	NM_001385203.1		c.2864C>T	p.Ala955Val	missense	Exon 21 of 26	NP_001372132.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TYK2	ENST00000525621.6	TSL:1 MANE Select	c.2783C>T	p.Ala928Val	missense	Exon 20 of 25	ENSP00000431885.1	P29597
	TYK2	ENST00000524462.5	TSL:1	c.2228C>T	p.Ala743Val	missense	Exon 16 of 21	ENSP00000433203.1	E9PM19
	TYK2	ENST00000531836.7	TSL:4	c.2783C>T	p.Ala928Val	missense	Exon 20 of 25	ENSP00000436175.2	P29597

Frequencies

GnomAD3 genomes AF: 0.00474 AC: 722 AN: 152182 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.00145

Gnomad AMI AF: 0.0263

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00433

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00805

Gnomad OTH AF: 0.00573

GnomAD2 exomes AF: 0.00464 AC: 1164 AN: 250964 AF XY: 0.00458

Gnomad AFR exome AF: 0.00111

Gnomad AMR exome AF: 0.00202

Gnomad ASJ exome AF: 0.00159

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00499

Gnomad NFE exome AF: 0.00802

Gnomad OTH exome AF: 0.00391

GnomAD4 exome AF: 0.00651 AC: 9519 AN: 1461510 Hom.: 46 Cov.: 33 AF XY: 0.00638 AC XY: 4642 AN XY: 727068

African (AFR) AF: 0.000926 AC: 31 AN: 33480

American (AMR) AF: 0.00190 AC: 85 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00226 AC: 59 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000661 AC: 57 AN: 86248

European-Finnish (FIN) AF: 0.00659 AC: 350 AN: 53090

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5762

European-Non Finnish (NFE) AF: 0.00782 AC: 8698 AN: 1111982

Other (OTH) AF: 0.00392 AC: 237 AN: 60394

GnomAD4 genome AF: 0.00474 AC: 722 AN: 152300 Hom.: 8 Cov.: 32 AF XY: 0.00420 AC XY: 313 AN XY: 74468

African (AFR) AF: 0.00144 AC: 60 AN: 41562

American (AMR) AF: 0.00144 AC: 22 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 9 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00433 AC: 46 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00806 AC: 548 AN: 68032

Other (OTH) AF: 0.00567 AC: 12 AN: 2116

Alfa AF: 0.00668 Hom.: 16

Bravo AF: 0.00453

TwinsUK AF: 0.00701 AC: 26

ALSPAC AF: 0.00960 AC: 37

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.00791 AC: 68

ExAC AF: 0.00510 AC: 619

EpiCase AF: 0.00671

EpiControl AF: 0.00646

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Immunodeficiency 35 (3)
-	-	3	not provided (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.46	T
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.33	D
MetaRNN	Benign	0.016	T
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Benign	1.9	L
PhyloP100		9.5
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-3.7	D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.91
MVP		0.91
MPC		0.94
ClinPred		0.031	T
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.90
gMVP		0.80
Mutation Taster		=82/18	polymorphism

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

Other links and lift over

dbSNP: rs35018800; hg19: chr19-10464843; COSMIC: COSV53386305; COSMIC: COSV53386305;