chr2-143033445-G-T

Variant names:

• chr2-143033445-G-T
• rs2304700
• NM_003937.3:c.1041+124G>T

Variant summary

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

The NM_003937.3(KYNU):​c.1041+124G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.121 in 810,176 control chromosomes in the GnomAD database, including 6,731 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.12 (1127 hom., cov: 32)
  • Exomes 𝑓: 0.12 (5604 hom.)
• Consequence: KYNU NM_003937.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.342
• Publications: 16 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 (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.239 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KYNU	NM_003937.3	c.1041+124G>T		intron_variant	Intron 12 of 13	ENST00000264170.9	NP_003928.1
KYNU	NM_001199241.2	c.1041+124G>T		intron_variant	Intron 13 of 14		NP_001186170.1
KYNU	XM_047446250.1	c.1041+124G>T		intron_variant	Intron 12 of 12		XP_047302206.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KYNU	ENST00000264170.9	c.1041+124G>T		intron_variant	Intron 12 of 13	1	NM_003937.3	ENSP00000264170.4
KYNU	ENST00000409512.5	c.1041+124G>T		intron_variant	Intron 13 of 14	1		ENSP00000386731.1

Frequencies

GnomAD3 genomes AF: 0.117 AC: 17839 AN: 152084 Hom.: 1125 Cov.: 32

Gnomad AFR AF: 0.111

Gnomad AMI AF: 0.0901

Gnomad AMR AF: 0.103

Gnomad ASJ AF: 0.0663

Gnomad EAS AF: 0.249

Gnomad SAS AF: 0.134

Gnomad FIN AF: 0.0733

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.123

Gnomad OTH AF: 0.115

GnomAD4 exome AF: 0.122 AC: 80001 AN: 657974 Hom.: 5604 AF XY: 0.122 AC XY: 43537 AN XY: 355966

African (AFR) AF: 0.112 AC: 2015 AN: 18036

American (AMR) AF: 0.0814 AC: 3507 AN: 43100

Ashkenazi Jewish (ASJ) AF: 0.0650 AC: 1346 AN: 20710

East Asian (EAS) AF: 0.267 AC: 9568 AN: 35866

South Asian (SAS) AF: 0.127 AC: 8798 AN: 69052

European-Finnish (FIN) AF: 0.0797 AC: 4136 AN: 51864

Middle Eastern (MID) AF: 0.0929 AC: 388 AN: 4178

European-Non Finnish (NFE) AF: 0.121 AC: 46055 AN: 381296

Other (OTH) AF: 0.124 AC: 4188 AN: 33872

GnomAD4 genome AF: 0.117 AC: 17865 AN: 152202 Hom.: 1127 Cov.: 32 AF XY: 0.116 AC XY: 8613 AN XY: 74416

African (AFR) AF: 0.111 AC: 4602 AN: 41518

American (AMR) AF: 0.103 AC: 1581 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0663 AC: 230 AN: 3468

East Asian (EAS) AF: 0.250 AC: 1294 AN: 5176

South Asian (SAS) AF: 0.134 AC: 645 AN: 4822

European-Finnish (FIN) AF: 0.0733 AC: 777 AN: 10600

Middle Eastern (MID) AF: 0.0884 AC: 26 AN: 294

European-Non Finnish (NFE) AF: 0.123 AC: 8380 AN: 68004

Other (OTH) AF: 0.117 AC: 248 AN: 2114

Alfa AF: 0.113 Hom.: 1770

Bravo AF: 0.118

Asia WGS AF: 0.182 AC: 634 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.43
DANN	Benign	0.49
PhyloP100		-0.34
Mutation Taster		=100/0	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: rs2304700; hg19: chr2-143791014; COSMIC: COSV51583020;