rs280520

Variant names:

• chr19-10362462-A-G
• rs280520
• NM_003331.5:c.1477-6T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003331.5(TYK2):​c.1477-6T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.249 in 1,591,026 control chromosomes in the GnomAD database, including 51,487 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (6416 hom., cov: 32)
  • Exomes 𝑓: 0.25 (45071 hom.)
• Consequence: TYK2 NM_003331.5 splice_region, intron
• Scores: Splicing: ADA: 0.00004761
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -6.71
• Publications: 20 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 19-10362462-A-G is Benign according to our data. Variant chr19-10362462-A-G is described in ClinVar as Benign. ClinVar VariationId is 137865.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.41 is higher than 0.05.

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.1477-6T>C		splice_region intron	N/A	NP_003322.3
	TYK2	NM_001385204.1		c.1477-6T>C		splice_region intron	N/A	NP_001372133.1
	TYK2	NM_001385203.1		c.1477-6T>C		splice_region intron	N/A	NP_001372132.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TYK2	ENST00000525621.6	TSL:1 MANE Select	c.1477-6T>C		splice_region intron	N/A	ENSP00000431885.1	P29597
	TYK2	ENST00000524462.5	TSL:1	c.922-6T>C		splice_region intron	N/A	ENSP00000433203.1	E9PM19
	TYK2	ENST00000531836.7	TSL:4	c.1477-6T>C		splice_region intron	N/A	ENSP00000436175.2	P29597

Frequencies

GnomAD3 genomes AF: 0.281 AC: 42697 AN: 151858 Hom.: 6396 Cov.: 32

Gnomad AFR AF: 0.379

Gnomad AMI AF: 0.164

Gnomad AMR AF: 0.220

Gnomad ASJ AF: 0.215

Gnomad EAS AF: 0.425

Gnomad SAS AF: 0.330

Gnomad FIN AF: 0.290

Gnomad MID AF: 0.285

Gnomad NFE AF: 0.225

Gnomad OTH AF: 0.269

GnomAD2 exomes AF: 0.264 AC: 56952 AN: 216126 AF XY: 0.264

Gnomad AFR exome AF: 0.381

Gnomad AMR exome AF: 0.194

Gnomad ASJ exome AF: 0.216

Gnomad EAS exome AF: 0.421

Gnomad FIN exome AF: 0.294

Gnomad NFE exome AF: 0.227

Gnomad OTH exome AF: 0.255

GnomAD4 exome AF: 0.246 AC: 353344 AN: 1439048 Hom.: 45071 Cov.: 39 AF XY: 0.247 AC XY: 175862 AN XY: 713318

African (AFR) AF: 0.390 AC: 12893 AN: 33092

American (AMR) AF: 0.197 AC: 8114 AN: 41168

Ashkenazi Jewish (ASJ) AF: 0.214 AC: 5469 AN: 25614

East Asian (EAS) AF: 0.401 AC: 15537 AN: 38730

South Asian (SAS) AF: 0.314 AC: 26374 AN: 83932

European-Finnish (FIN) AF: 0.288 AC: 14886 AN: 51754

Middle Eastern (MID) AF: 0.265 AC: 1518 AN: 5720

European-Non Finnish (NFE) AF: 0.230 AC: 252740 AN: 1099564

Other (OTH) AF: 0.266 AC: 15813 AN: 59474

GnomAD4 genome AF: 0.281 AC: 42773 AN: 151978 Hom.: 6416 Cov.: 32 AF XY: 0.284 AC XY: 21070 AN XY: 74274

African (AFR) AF: 0.379 AC: 15719 AN: 41460

American (AMR) AF: 0.220 AC: 3356 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.215 AC: 746 AN: 3470

East Asian (EAS) AF: 0.425 AC: 2192 AN: 5156

South Asian (SAS) AF: 0.329 AC: 1582 AN: 4814

European-Finnish (FIN) AF: 0.290 AC: 3067 AN: 10562

Middle Eastern (MID) AF: 0.282 AC: 83 AN: 294

European-Non Finnish (NFE) AF: 0.225 AC: 15304 AN: 67944

Other (OTH) AF: 0.273 AC: 575 AN: 2106

Alfa AF: 0.239 Hom.: 1832

Bravo AF: 0.282

Asia WGS AF: 0.405 AC: 1402 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	Immunodeficiency 35 (3)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.072
DANN	Benign	0.32
PhyloP100		-6.7
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000048
dbscSNV1_RF	Benign	0.0
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: rs280520; hg19: chr19-10473138; COSMIC: COSV53384706; COSMIC: COSV53384706;