2-142957696-G-A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBS1_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. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars). 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

Scores

Clinical Significance

Uncertain significance no assertion criteria provided U:2

Conservation

PhyloP100: 2.23

Publications

16 publications found

Variant links:

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: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), 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

KYNU links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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 passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
KYNU	NM_003937.3	MANE Select	c.563G>A	p.Arg188Gln	missense	Exon 7 of 14	NP_003928.1
KYNU	NM_001199241.2		c.563G>A	p.Arg188Gln	missense	Exon 8 of 15	NP_001186170.1
KYNU	NM_001032998.2		c.563G>A	p.Arg188Gln	missense	Exon 7 of 12	NP_001028170.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
KYNU	ENST00000264170.9	TSL:1 MANE Select	c.563G>A	p.Arg188Gln	missense	Exon 7 of 14	ENSP00000264170.4
KYNU	ENST00000409512.5	TSL:1	c.563G>A	p.Arg188Gln	missense	Exon 8 of 15	ENSP00000386731.1
KYNU	ENST00000375773.6	TSL:1	c.563G>A	p.Arg188Gln	missense	Exon 7 of 12	ENSP00000364928.2

Frequencies

GnomAD3 genomes

AF:

0.000322

AC:

AN:

151986

Hom.:

Cov.:

show subpopulations

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

show subpopulations

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.:

Cov.:

AF XY:

0.000265

AC XY:

191

AN XY:

721600

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33170

American (AMR)

AF:

0.00228

AC:

102

AN:

44692

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26028

East Asian (EAS)

AF:

0.00658

AC:

260

AN:

39484

South Asian (SAS)

AF:

0.000174

AC:

AN:

85974

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53258

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5732

European-Non Finnish (NFE)

AF:

0.00000545

AC:

AN:

1100312

Other (OTH)

AF:

0.000351

AC:

AN:

59910

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

106

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000322

AC:

AN:

152104

Hom.:

Cov.:

AF XY:

0.000390

AC XY:

AN XY:

74364

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41508

American (AMR)

AF:

0.000458

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00714

AC:

AN:

5182

South Asian (SAS)

AF:

0.00104

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10582

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67964

Other (OTH)

AF:

0.00

AC:

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000438

Hom.:

Bravo

AF:

0.000582

ExAC

AF:

0.000857

AC:

104

Asia WGS

AF:

0.00231

AC:

AN:

3470

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: no assertion criteria provided

LINK: link

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 v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.38

Eigen

Benign

-0.18

Eigen_PC

Benign

-0.077

FATHMM_MKL

Uncertain

0.81

LIST_S2

Uncertain

0.95

M_CAP

Benign

0.024

MetaRNN

Benign

0.0046

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

PhyloP100

2.2

PrimateAI

Benign

0.29

PROVEAN

Benign

0.070

REVEL

Benign

0.061

Sift

Uncertain

0.011

Sift4G

Uncertain

0.0030

Polyphen

0.30

Vest4

0.094

MVP

0.64

MPC

0.039

ClinPred

0.078

GERP RS

1.8

Varity_R

0.11

gMVP

0.73

Mutation Taster

=84/16

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over