rs2304705

chr2-142957696-G-Achr2-142957696-G-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BS1_Supporting

The NM_003937.3(KYNU):c.563G>A(p.Arg188Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000284 in 1,600,664 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R188W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00032 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00028 (1 hom.)
• Consequence: KYNU NM_003937.3 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:2
• Conservation: PhyloP100: 2.23

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]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0045943856).
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000322 (49/152104) while in subpopulation EAS AF= 0.00714 (37/5182). AF 95% confidence interval is 0.00532. There are 0 homozygotes in gnomad4. There are 29 alleles in male gnomad4 subpopulation. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KYNU	NM_003937.3	c.563G>A	p.Arg188Gln	missense_variant	7/14	ENST00000264170.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KYNU	ENST00000264170.9	c.563G>A	p.Arg188Gln	missense_variant	7/14	1	NM_003937.3	P1

Frequencies

GnomAD3 genomes AF: 0.000322 AC: 49 AN: 151986 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000459

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00712

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000906 AC: 227 AN: 250470 Hom.: 0 AF XY: 0.000857 AC XY: 116 AN XY: 135374

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00269

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00709

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000280 AC: 405 AN: 1448560 Hom.: 1 Cov.: 27 AF XY: 0.000265 AC XY: 191 AN XY: 721600

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00228

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00658

Gnomad4 SAS exome AF: 0.000174

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000545

Gnomad4 OTH exome AF: 0.000351

GnomAD4 genome AF: 0.000322 AC: 49 AN: 152104 Hom.: 0 Cov.: 32 AF XY: 0.000390 AC XY: 29 AN XY: 74364

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00714

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000511 Hom.: 2

Bravo AF: 0.000582

ExAC AF: 0.000857 AC: 104

Asia WGS AF: 0.00231 AC: 8 AN: 3470

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: no assertion criteria provided

Submissions by phenotype

Vertebral, cardiac, renal, and limb defects syndrome 2 Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Zotz-Klimas Genetics Lab, MVZ Zotz Klimas

Oct 30, 2023

- -

not provided Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

OMIM

Dec 01, 2011

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.38	T;.;T;.
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.077
FATHMM_MKL	Uncertain	0.81	D
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.0046	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L;L;L;.
MutationTaster	Benign	0.61	D;D;D
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.070	N;N;N;.
REVEL	Benign	0.061
Sift	Uncertain	0.011	D;D;D;.
Sift4G	Uncertain	0.0030	D;D;D;D
Polyphen		0.30	B;.;B;.
Vest4		0.094
MVP		0.64
MPC		0.039
ClinPred		0.078	T
GERP RS		1.8
Varity_R		0.11
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs2304705; hg19: chr2-143715265; COSMIC: COSV99932589; COSMIC: COSV99932589;