chr2-143040620-A-G

Variant names:

• chr2-143040620-A-G
• rs9013
• NM_003937.3:c.1234A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003937.3(KYNU):​c.1234A>G​(p.Lys412Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.171 in 1,606,390 control chromosomes in the GnomAD database, including 24,512 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.16 (1959 hom., cov: 32)
  • Exomes 𝑓: 0.17 (22553 hom.)
• Consequence: KYNU NM_003937.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.85
• Publications: 32 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: 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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0051650703).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.257 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KYNU	NM_003937.3	MANE Select	c.1234A>G	p.Lys412Glu	missense	Exon 13 of 14	NP_003928.1
	KYNU	NM_001199241.2		c.1234A>G	p.Lys412Glu	missense	Exon 14 of 15	NP_001186170.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KYNU	ENST00000264170.9	TSL:1 MANE Select	c.1234A>G	p.Lys412Glu	missense	Exon 13 of 14	ENSP00000264170.4
	KYNU	ENST00000409512.5	TSL:1	c.1234A>G	p.Lys412Glu	missense	Exon 14 of 15	ENSP00000386731.1

Frequencies

GnomAD3 genomes AF: 0.157 AC: 23861 AN: 151946 Hom.: 1954 Cov.: 32

Gnomad AFR AF: 0.132

Gnomad AMI AF: 0.120

Gnomad AMR AF: 0.128

Gnomad ASJ AF: 0.0887

Gnomad EAS AF: 0.268

Gnomad SAS AF: 0.175

Gnomad FIN AF: 0.152

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.174

Gnomad OTH AF: 0.152

GnomAD2 exomes AF: 0.160 AC: 39410 AN: 246126 AF XY: 0.161

Gnomad AFR exome AF: 0.134

Gnomad AMR exome AF: 0.0982

Gnomad ASJ exome AF: 0.0895

Gnomad EAS exome AF: 0.279

Gnomad FIN exome AF: 0.155

Gnomad NFE exome AF: 0.167

Gnomad OTH exome AF: 0.154

GnomAD4 exome AF: 0.172 AC: 250241 AN: 1454326 Hom.: 22553 Cov.: 31 AF XY: 0.172 AC XY: 124012 AN XY: 722906

African (AFR) AF: 0.128 AC: 4256 AN: 33200

American (AMR) AF: 0.102 AC: 4475 AN: 43882

Ashkenazi Jewish (ASJ) AF: 0.0908 AC: 2345 AN: 25832

East Asian (EAS) AF: 0.290 AC: 11486 AN: 39566

South Asian (SAS) AF: 0.173 AC: 14726 AN: 85272

European-Finnish (FIN) AF: 0.154 AC: 8207 AN: 53292

Middle Eastern (MID) AF: 0.109 AC: 622 AN: 5732

European-Non Finnish (NFE) AF: 0.175 AC: 193797 AN: 1107502

Other (OTH) AF: 0.172 AC: 10327 AN: 60048

GnomAD4 genome AF: 0.157 AC: 23901 AN: 152064 Hom.: 1959 Cov.: 32 AF XY: 0.157 AC XY: 11643 AN XY: 74356

African (AFR) AF: 0.133 AC: 5520 AN: 41510

American (AMR) AF: 0.128 AC: 1955 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.0887 AC: 308 AN: 3472

East Asian (EAS) AF: 0.269 AC: 1391 AN: 5176

South Asian (SAS) AF: 0.174 AC: 840 AN: 4826

European-Finnish (FIN) AF: 0.152 AC: 1608 AN: 10596

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.174 AC: 11819 AN: 67938

Other (OTH) AF: 0.154 AC: 324 AN: 2106

Alfa AF: 0.165 Hom.: 5432

Bravo AF: 0.152

TwinsUK AF: 0.174 AC: 647

ALSPAC AF: 0.179 AC: 690

ESP6500AA AF: 0.139 AC: 614

ESP6500EA AF: 0.172 AC: 1481

ExAC AF: 0.162 AC: 19625

Asia WGS AF: 0.209 AC: 726 AN: 3478

EpiCase AF: 0.169

EpiControl AF: 0.160

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	13
DANN	Benign	0.23
DEOGEN2	Benign	0.037	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.56	T
MetaRNN	Benign	0.0052	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L
PhyloP100		1.8
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.098
Sift	Benign	0.69	T
Sift4G	Benign	0.52	T
Polyphen		0.0	B
Vest4		0.17
MPC		0.044
ClinPred		0.0045	T
GERP RS		4.4
Varity_R		0.18
gMVP		0.54
Mutation Taster		=97/3	polymorphism (auto)

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: rs9013; hg19: chr2-143798189; COSMIC: COSV51580314;