19-10380663-A-T

Variant names:

• chr19-10380663-A-T
• rs12720217
• NM_003331.5:c.-469T>A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM2 BP4_Strong BS1

The NM_003331.5(TYK2):​c.-469T>A variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00239 in 85,332 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0024 (0 hom., cov: 25)
  • Exomes 𝑓: 0.011 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TYK2 NM_003331.5 upstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.69

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 Likely_benign. Variant got -6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00239 (204/85332) while in subpopulation AFR AF= 0.00525 (88/16760). AF 95% confidence interval is 0.00436. There are 0 homozygotes in gnomad4. There are 105 alleles in male gnomad4 subpopulation. Median coverage is 25. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TYK2	NM_003331.5	c.-469T>A		upstream_gene_variant		ENST00000525621.6	NP_003322.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TYK2	ENST00000525621.6	c.-469T>A		upstream_gene_variant		1	NM_003331.5	ENSP00000431885.1

Frequencies

GnomAD3 genomes AF: 0.00238 AC: 203 AN: 85344 Hom.: 0 Cov.: 25

Gnomad AFR AF: 0.00520

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000887

Gnomad ASJ AF: 0.000470

Gnomad EAS AF: 0.000306

Gnomad SAS AF: 0.00154

Gnomad FIN AF: 0.00452

Gnomad MID AF: 0.0235

Gnomad NFE AF: 0.00157

Gnomad OTH AF: 0.00494

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0114 AC: 1 AN: 88 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 60

Gnomad4 AFR exome AF: 0.00

Gnomad4 EAS exome AF: 0.0185

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

GnomAD4 genome AF: 0.00239 AC: 204 AN: 85332 Hom.: 0 Cov.: 25 AF XY: 0.00254 AC XY: 105 AN XY: 41304

Gnomad4 AFR AF: 0.00525

Gnomad4 AMR AF: 0.000885

Gnomad4 ASJ AF: 0.000470

Gnomad4 EAS AF: 0.000307

Gnomad4 SAS AF: 0.00116

Gnomad4 FIN AF: 0.00452

Gnomad4 NFE AF: 0.00157

Gnomad4 OTH AF: 0.00575

Alfa AF: 0.0242 Hom.: 29

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.18
DANN	Benign	0.66

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs12720217; hg19: chr19-10491339;