rs280500

Variant names:

• chr19-10379726-A-G
• rs280500
• NM_003331.5:c.-132T>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.-132T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.192 in 152,152 control chromosomes in the GnomAD database, including 3,251 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (3251 hom., cov: 31)
  • Exomes 𝑓: 0.12 (0 hom.)
• Consequence: TYK2 NM_003331.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.256
• Publications: 34 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=-0.88).
• BP6: Variant 19-10379726-A-G is Benign according to our data. Variant chr19-10379726-A-G is described in ClinVar as Benign. ClinVar VariationId is 327965.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.296 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.-132T>C		5_prime_UTR	Exon 2 of 25	NP_003322.3
	TYK2	NM_001385204.1		c.-132T>C		5_prime_UTR	Exon 2 of 25	NP_001372133.1
	TYK2	NM_001385203.1		c.-132T>C		5_prime_UTR	Exon 2 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.-132T>C		5_prime_UTR	Exon 2 of 25	ENSP00000431885.1	P29597
	TYK2	ENST00000524462.5	TSL:1	c.-91+784T>C		intron	N/A	ENSP00000433203.1	E9PM19
	TYK2	ENST00000907163.1		c.-132T>C		5_prime_UTR	Exon 2 of 25	ENSP00000577222.1

Frequencies

GnomAD3 genomes AF: 0.191 AC: 29078 AN: 151904 Hom.: 3240 Cov.: 31

Gnomad AFR AF: 0.300

Gnomad AMI AF: 0.0932

Gnomad AMR AF: 0.127

Gnomad ASJ AF: 0.166

Gnomad EAS AF: 0.0346

Gnomad SAS AF: 0.191

Gnomad FIN AF: 0.186

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.155

Gnomad OTH AF: 0.175

GnomAD4 exome AF: 0.115 AC: 15 AN: 130 Hom.: 0 Cov.: 0 AF XY: 0.143 AC XY: 10 AN XY: 70

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.0984 AC: 12 AN: 122

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.333 AC: 2 AN: 6

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.500 AC: 1 AN: 2

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.192 AC: 29134 AN: 152022 Hom.: 3251 Cov.: 31 AF XY: 0.190 AC XY: 14081 AN XY: 74286

African (AFR) AF: 0.301 AC: 12460 AN: 41414

American (AMR) AF: 0.127 AC: 1932 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.166 AC: 577 AN: 3470

East Asian (EAS) AF: 0.0345 AC: 179 AN: 5194

South Asian (SAS) AF: 0.191 AC: 918 AN: 4818

European-Finnish (FIN) AF: 0.186 AC: 1972 AN: 10578

Middle Eastern (MID) AF: 0.228 AC: 67 AN: 294

European-Non Finnish (NFE) AF: 0.155 AC: 10566 AN: 67984

Other (OTH) AF: 0.179 AC: 378 AN: 2114

Alfa AF: 0.164 Hom.: 4196

Bravo AF: 0.190

Asia WGS AF: 0.143 AC: 494 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	9.4
DANN	Benign	0.74
PhyloP100		0.26
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs280500; hg19: chr19-10490402;