rs6743085

Variant names:

• chr2-142960626-G-A
• rs6743085
• NM_003937.3:c.585G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_003937.3(KYNU):​c.585G>A​(p.Gly195Gly) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.001 in 1,613,132 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0054 (6 hom., cov: 32)
  • Exomes 𝑓: 0.00054 (9 hom.)
• Consequence: KYNU NM_003937.3 splice_region, synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.490
• Publications: 1 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 2-142960626-G-A is Benign according to our data. Variant chr2-142960626-G-A is described in ClinVar as Benign. ClinVar VariationId is 711853.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.49 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00538 (818/152110) while in subpopulation AFR AF = 0.0188 (781/41476). AF 95% confidence interval is 0.0177. There are 6 homozygotes in GnomAd4. There are 372 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 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.585G>A	p.Gly195Gly	splice_region synonymous	Exon 8 of 14	NP_003928.1	Q16719-1
	KYNU	NM_001199241.2		c.585G>A	p.Gly195Gly	splice_region synonymous	Exon 9 of 15	NP_001186170.1	Q16719-1
	KYNU	NM_001032998.2		c.585G>A	p.Gly195Gly	splice_region synonymous	Exon 8 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.585G>A	p.Gly195Gly	splice_region synonymous	Exon 8 of 14	ENSP00000264170.4	Q16719-1
	KYNU	ENST00000409512.5	TSL:1	c.585G>A	p.Gly195Gly	splice_region synonymous	Exon 9 of 15	ENSP00000386731.1	Q16719-1
	KYNU	ENST00000375773.6	TSL:1	c.585G>A	p.Gly195Gly	splice_region synonymous	Exon 8 of 12	ENSP00000364928.2	Q16719-2

Frequencies

GnomAD3 genomes AF: 0.00535 AC: 813 AN: 151992 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.0188

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00184

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00140 AC: 352 AN: 250950 AF XY: 0.000907

Gnomad AFR exome AF: 0.0197

Gnomad AMR exome AF: 0.000608

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000441

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000544 AC: 795 AN: 1461022 Hom.: 9 Cov.: 30 AF XY: 0.000455 AC XY: 331 AN XY: 726850

African (AFR) AF: 0.0196 AC: 656 AN: 33454

American (AMR) AF: 0.000693 AC: 31 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39664

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86222

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53374

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5764

European-Non Finnish (NFE) AF: 0.0000207 AC: 23 AN: 1111370

Other (OTH) AF: 0.00133 AC: 80 AN: 60352

GnomAD4 genome AF: 0.00538 AC: 818 AN: 152110 Hom.: 6 Cov.: 32 AF XY: 0.00500 AC XY: 372 AN XY: 74364

African (AFR) AF: 0.0188 AC: 781 AN: 41476

American (AMR) AF: 0.00183 AC: 28 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10572

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68006

Other (OTH) AF: 0.00378 AC: 8 AN: 2116

Alfa AF: 0.00219 Hom.: 10

Bravo AF: 0.00636

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

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
BayesDel_noAF	Benign	-0.52
CADD	Benign	5.5
DANN	Benign	0.69
PhyloP100		-0.49
Mutation Taster		=94/6	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: rs6743085; hg19: chr2-143718195;