rs770927552
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_003331.5(TYK2):c.209_212del(p.Cys70SerfsTer21) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000157 in 1,461,864 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 31)
Exomes 𝑓: 0.000016 ( 0 hom. )
Consequence
TYK2
NM_003331.5 frameshift
NM_003331.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 3.88
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 19-10368399-GAAGC-G is Pathogenic according to our data. Variant chr19-10368399-GAAGC-G is described in ClinVar as [Pathogenic]. Clinvar id is 225508.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TYK2 | NM_003331.5 | c.209_212del | p.Cys70SerfsTer21 | frameshift_variant | 4/25 | ENST00000525621.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TYK2 | ENST00000525621.6 | c.209_212del | p.Cys70SerfsTer21 | frameshift_variant | 4/25 | 1 | NM_003331.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD3 genomes
?
Cov.:
31
GnomAD3 exomes AF: 0.0000477 AC: 12AN: 251474Hom.: 0 AF XY: 0.0000515 AC XY: 7AN XY: 135920
GnomAD3 exomes
AF:
AC:
12
AN:
251474
Hom.:
AF XY:
AC XY:
7
AN XY:
135920
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.0000157 AC: 23AN: 1461864Hom.: 0 AF XY: 0.0000193 AC XY: 14AN XY: 727228
GnomAD4 exome
AF:
AC:
23
AN:
1461864
Hom.:
AF XY:
AC XY:
14
AN XY:
727228
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome ? Cov.: 31
GnomAD4 genome
?
Cov.:
31
Bravo
AF:
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Immunodeficiency 35 Pathogenic:3
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 01, 2006 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 27, 2023 | This sequence change creates a premature translational stop signal (p.Cys70Serfs*21) in the TYK2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TYK2 are known to be pathogenic (PMID: 22402565, 26304966). This variant is present in population databases (rs770927552, gnomAD 0.07%). This premature translational stop signal has been observed in individual(s) with mendelian susceptibility to mycobacterial disease (PMID: 29725107). ClinVar contains an entry for this variant (Variation ID: 225508). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | reference population | Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center | Mar 18, 2016 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 30, 2017 | The c.209_212delGCTT variant in the TYK2 gene has been reported previously in the homozygous state in an individual with hyper-IgE syndrome (Minegishi et al., 2006). The c.209_212delGCTT variant causes a frameshift starting with codon Cysteine 70, changes this amino acid to a Serine residue, and creates a premature Stop codon at position 21 of the new reading frame, denoted p.Cys70SerfsX21. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.209_212delGCTT variant is observed in 12/17248 (0.07%) alleles, although not in the homozygous state, from individuals of East Asian background, in large population cohorts (Lek et al., 2016). We interpret c.209_212delGCTT as a pathogenic variant. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at