chr2-142885441-C-T

Variant names:

• chr2-142885441-C-T
• rs199895914
• NM_003937.3:c.74C>T

Variant summary

Our verdict is Benign. The variant received -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. 14/21 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
• Publications: 4 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: Benign. The variant received -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 29. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 22 AR gene

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.74C>T	p.Thr25Met	missense	Exon 2 of 14	NP_003928.1	Q16719-1
	KYNU	NM_001199241.2		c.74C>T	p.Thr25Met	missense	Exon 3 of 15	NP_001186170.1	Q16719-1
	KYNU	NM_001032998.2		c.74C>T	p.Thr25Met	missense	Exon 2 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.74C>T	p.Thr25Met	missense	Exon 2 of 14	ENSP00000264170.4	Q16719-1
	KYNU	ENST00000409512.5	TSL:1	c.74C>T	p.Thr25Met	missense	Exon 3 of 15	ENSP00000386731.1	Q16719-1
	KYNU	ENST00000375773.6	TSL:1	c.74C>T	p.Thr25Met	missense	Exon 2 of 12	ENSP00000364928.2	Q16719-2

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

GnomAD2 exomes AF: 0.00187 AC: 469 AN: 251458 AF XY: 0.00246

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 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

African (AFR) AF: 0.0000896 AC: 3 AN: 33470

American (AMR) AF: 0.00114 AC: 51 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.0128 AC: 1106 AN: 86238

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53416

Middle Eastern (MID) AF: 0.00191 AC: 11 AN: 5746

European-Non Finnish (NFE) AF: 0.000196 AC: 218 AN: 1111492

Other (OTH) AF: 0.000961 AC: 58 AN: 60378

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

African (AFR) AF: 0.0000962 AC: 4 AN: 41560

American (AMR) AF: 0.00 AC: 0 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5154

South Asian (SAS) AF: 0.0127 AC: 61 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000456 AC: 31 AN: 68022

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000545 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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	0.16
Eigen_PC	Benign	0.086
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.74	T
MetaRNN	Benign	0.0083	T
MetaSVM	Benign	-0.71	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		1.7
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.19
Sift	Uncertain	0.016	D
Sift4G	Uncertain	0.035	D
Polyphen		0.98	D
Vest4		0.44
MVP		0.79
MPC		0.061
ClinPred		0.074	T
GERP RS		5.0
PromoterAI		-0.020	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.11
gMVP		0.42
Mutation Taster		=92/8	polymorphism

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: rs199895914; hg19: chr2-143643010;