NM_003331.5:c.-482A>C

Variant names:

• chr19-10380676-T-G
• rs2304259
• NM_003331.5:c.-482A>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_003331.5(TYK2):​c.-482A>C variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000133 in 150,928 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: 𝑓 0.00013 (1 hom., cov: 30)
  • Exomes 𝑓: 0.022 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TYK2 NM_003331.5 upstream_gene
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: -1.87
• Publications: 6 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).

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.-482A>C		upstream_gene	N/A	NP_003322.3
	TYK2	NM_001385204.1		c.-482A>C		upstream_gene	N/A	NP_001372133.1
	TYK2	NM_001385203.1		c.-482A>C		upstream_gene	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.-482A>C		upstream_gene	N/A	ENSP00000431885.1	P29597
	TYK2	ENST00000524462.5	TSL:1	c.-257A>C		upstream_gene	N/A	ENSP00000433203.1	E9PM19
	TYK2	ENST00000531836.7	TSL:4	c.-392A>C		upstream_gene	N/A	ENSP00000436175.2	P29597

Frequencies

GnomAD3 genomes AF: 0.000133 AC: 20 AN: 150824 Hom.: 1 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000660

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000785

Gnomad SAS AF: 0.000626

Gnomad FIN AF: 0.000195

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.000965

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0217 AC: 2 AN: 92 Hom.: 0 Cov.: 0 AF XY: 0.0323 AC XY: 2 AN XY: 62

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.0217 AC: 1 AN: 46

South Asian (SAS) AF: 0.0625 AC: 1 AN: 16

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 24

Other (OTH) AF: 0.00 AC: 0 AN: 2

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0385499), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000133 AC: 20 AN: 150928 Hom.: 1 Cov.: 30 AF XY: 0.000149 AC XY: 11 AN XY: 73644

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41160

American (AMR) AF: 0.0000659 AC: 1 AN: 15170

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.000787 AC: 4 AN: 5084

South Asian (SAS) AF: 0.000627 AC: 3 AN: 4786

European-Finnish (FIN) AF: 0.000195 AC: 2 AN: 10276

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 67698

Other (OTH) AF: 0.000956 AC: 2 AN: 2092

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000000000000111022), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.110 Hom.: 441

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	1	-	Virus-induced diabetes (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.48
DANN	Benign	0.38
PhyloP100		-1.9
PromoterAI		0.015	Neutral
Mutation Taster		=300/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs2304259; hg19: chr19-10491352;