2-142885441-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003937.3(KYNU):c.74C>T(p.Thr25Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000958 in 1,613,538 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00064 (1 hom., cov: 29)
  • Exomes 𝑓: 0.00099 (22 hom.)
• Consequence: KYNU NM_003937.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.67

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008279264).
• BP6: Variant 2-142885441-C-T is Benign according to our data. Variant chr2-142885441-C-T is described in ClinVar as [Benign]. Clinvar id is 789880.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000637 (97/152242) while in subpopulation SAS AF= 0.0127 (61/4816). AF 95% confidence interval is 0.0101. There are 1 homozygotes in gnomad4. There are 62 alleles in male gnomad4 subpopulation. Median coverage is 29. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KYNU	NM_003937.3	c.74C>T	p.Thr25Met	missense_variant	2/14	ENST00000264170.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KYNU	ENST00000264170.9	c.74C>T	p.Thr25Met	missense_variant	2/14	1	NM_003937.3	P1

Frequencies

GnomAD3 genomes AF: 0.000631 AC: 96 AN: 152124 Hom.: 1 Cov.: 29

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000456

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00187 AC: 469 AN: 251458 Hom.: 8 AF XY: 0.00246 AC XY: 334 AN XY: 135912

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00133

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0125

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000255

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.000992 AC: 1449 AN: 1461296 Hom.: 22 Cov.: 31 AF XY: 0.00137 AC XY: 999 AN XY: 727008

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.00114

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0128

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000196

Gnomad4 OTH exome AF: 0.000961

GnomAD4 genome AF: 0.000637 AC: 97 AN: 152242 Hom.: 1 Cov.: 29 AF XY: 0.000833 AC XY: 62 AN XY: 74422

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0127

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000456

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000463 Hom.: 0

Bravo AF: 0.000321

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00211 AC: 256

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000356

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Sep 19, 2018	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2022	KYNU: BP4, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.25
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.055	T;.;T;T;.
Eigen	Benign	0.16
Eigen_PC	Benign	0.086
FATHMM_MKL	Benign	0.18	N
MetaRNN	Benign	0.0083	T;T;T;T;T
MetaSVM	Benign	-0.71	T
MutationAssessor	Uncertain	2.7	M;M;M;.;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-2.0	N;N;N;N;.
REVEL	Benign	0.19
Sift	Uncertain	0.016	D;D;D;D;.
Sift4G	Uncertain	0.035	D;D;D;D;D
Polyphen		0.98	D;.;D;.;.
Vest4		0.44
MVP		0.79
MPC		0.061
ClinPred		0.074	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.11
gMVP		0.42

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

Publications

LitVar

Other links and lift over

dbSNP: rs199895914; hg19: chr2-143643010;