rs2304705

Variant names:

• chr2-142957696-G-A
• rs2304705
• NM_003937.3:c.563G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-142957696-G-A
• chr2-142957696-G-C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. 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. 16/23 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 the same amino acid substitution has been previously reported as Likely benign in 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

Our verdict: Likely_benign. The variant received -5 ACMG points.

• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KYNU	NM_003937.3	c.563G>A	p.Arg188Gln	missense_variant	Exon 7 of 14	ENST00000264170.9	NP_003928.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KYNU	ENST00000264170.9	c.563G>A	p.Arg188Gln	missense_variant	Exon 7 of 14	1	NM_003937.3	ENSP00000264170.4

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

GnomAD2 exomes AF: 0.000906 AC: 227 AN: 250470 AF XY: 0.000857

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 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 AC: 0 AN: 33170

Gnomad4 AMR exome AF: 0.00228 AC: 102 AN: 44692

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26028

Gnomad4 EAS exome AF: 0.00658 AC: 260 AN: 39484

Gnomad4 SAS exome AF: 0.000174 AC: 15 AN: 85974

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53258

Gnomad4 NFE exome AF: 0.00000545 AC: 6 AN: 1100312

Gnomad4 Remaining exome AF: 0.000351 AC: 21 AN: 59910

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 AC: 0 AN: 0

Gnomad4 AMR AF: 0.000458 AC: 0.000458295 AN: 0.000458295

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00714 AC: 0.0071401 AN: 0.0071401

Gnomad4 SAS AF: 0.00104 AC: 0.00103821 AN: 0.00103821

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.00 AC: 0 AN: 0

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.000438 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

Oct 30, 2023

Zotz-Klimas Genetics Lab, MVZ Zotz Klimas

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Uncertain:1

Dec 01, 2011

OMIM

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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
LIST_S2	Uncertain	0.95	.;D;D;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;.
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
Mutation Taster		=84/16	polymorphism

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;