2-142918694-A-AT
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_003937.3(KYNU):c.256dup(p.Tyr86LeufsTer3) variant causes a frameshift change. The variant allele was found at a frequency of 0.000158 in 1,612,620 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.00016 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00016 ( 0 hom. )
Consequence
KYNU
NM_003937.3 frameshift
NM_003937.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 6.59
Genes affected
KYNU (HGNC:6469): (kynureninase) Kynureninase is a pyridoxal-5'-phosphate (pyridoxal-P) dependent enzyme that catalyzes the cleavage of L-kynurenine and L-3-hydroxykynurenine into anthranilic and 3-hydroxyanthranilic acids, respectively. Kynureninase is involved in the biosynthesis of NAD cofactors from tryptophan through the kynurenine pathway. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2010]
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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
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Very rare variant in population databases, with high coverage;
PP5
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Variant 2-142918694-A-AT is Pathogenic according to our data. Variant chr2-142918694-A-AT is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1324639.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KYNU | NM_003937.3 | c.256dup | p.Tyr86LeufsTer3 | frameshift_variant | 3/14 | ENST00000264170.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KYNU | ENST00000264170.9 | c.256dup | p.Tyr86LeufsTer3 | frameshift_variant | 3/14 | 1 | NM_003937.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000158 AC: 24AN: 152168Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000799 AC: 20AN: 250196Hom.: 0 AF XY: 0.0000665 AC XY: 9AN XY: 135276
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GnomAD4 exome AF: 0.000157 AC: 230AN: 1460452Hom.: 0 Cov.: 34 AF XY: 0.000156 AC XY: 113AN XY: 726486
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Vertebral, cardiac, renal, and limb defects syndrome 2 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Aug 29, 2023 | Criteria applied: PVS1,PM2_SUP - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 30, 2022 | This sequence change creates a premature translational stop signal (p.Tyr86Leufs*3) in the KYNU gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in KYNU are known to be pathogenic (PMID: 17334708, 28792876, 31923704, 34200361). This variant is present in population databases (rs550079487, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with KYNU-related conditions. ClinVar contains an entry for this variant (Variation ID: 1324639). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at