chr2-142918694-A-AT

Variant names:

• chr2-142918694-A-AT
• rs550079487
• NM_003937.3:c.256dupT

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_003937.3(KYNU):​c.256dupT​(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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 6.59
• Publications: 0 publications found

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]

KYNU Gene-Disease associations (from GenCC):

• vertebral, cardiac, renal, and limb defects syndrome 2

  Inheritance: AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, ClinGen
• encephalopathy due to hydroxykynureninuria

  Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• congenital vertebral-cardiac-renal anomalies syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 2-142918694-A-AT is Pathogenic according to our data. Variant chr2-142918694-A-AT is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1324639.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003937.3. 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
	KYNU	NM_003937.3	MANE Select	c.256dupT	p.Tyr86LeufsTer3	frameshift	Exon 3 of 14	NP_003928.1	Q16719-1
	KYNU	NM_001199241.2		c.256dupT	p.Tyr86LeufsTer3	frameshift	Exon 4 of 15	NP_001186170.1	Q16719-1
	KYNU	NM_001032998.2		c.256dupT	p.Tyr86LeufsTer3	frameshift	Exon 3 of 12	NP_001028170.1	Q16719-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KYNU	ENST00000264170.9	TSL:1 MANE Select	c.256dupT	p.Tyr86LeufsTer3	frameshift	Exon 3 of 14	ENSP00000264170.4	Q16719-1
	KYNU	ENST00000409512.5	TSL:1	c.256dupT	p.Tyr86LeufsTer3	frameshift	Exon 4 of 15	ENSP00000386731.1	Q16719-1
	KYNU	ENST00000375773.6	TSL:1	c.256dupT	p.Tyr86LeufsTer3	frameshift	Exon 3 of 12	ENSP00000364928.2	Q16719-2

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152168 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000799 AC: 20 AN: 250196 AF XY: 0.0000665

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000995

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000159

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000157 AC: 230 AN: 1460452 Hom.: 0 Cov.: 34 AF XY: 0.000156 AC XY: 113 AN XY: 726486

African (AFR) AF: 0.00 AC: 0 AN: 33426

American (AMR) AF: 0.00 AC: 0 AN: 44638

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26082

East Asian (EAS) AF: 0.00 AC: 0 AN: 39578

South Asian (SAS) AF: 0.00 AC: 0 AN: 85976

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53390

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.000206 AC: 229 AN: 1111282

Other (OTH) AF: 0.00 AC: 0 AN: 60324

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152168 Hom.: 0 Cov.: 33 AF XY: 0.000161 AC XY: 12 AN XY: 74336

African (AFR) AF: 0.0000482 AC: 2 AN: 41456

American (AMR) AF: 0.00 AC: 0 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000309 AC: 21 AN: 68030

Other (OTH) AF: 0.000478 AC: 1 AN: 2094

Alfa AF: 0.000109 Hom.: 0

Bravo AF: 0.0000945

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)
1	-	-	Vertebral, cardiac, renal, and limb defects syndrome 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.6
Mutation Taster		=7/193	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs550079487; hg19: chr2-143676263;