2-27087015-G-A

Position:

• chr2-27087015-G-A

Variant summary

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

The NM_006488.3(KHK):​c.-245G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00938 in 424,554 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0077 (8 hom., cov: 33)
  • Exomes 𝑓: 0.010 (34 hom.)
• Consequence: KHK NM_006488.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.743

Genes affected

KHK (HGNC:6315): (ketohexokinase) This gene encodes ketohexokinase that catalyzes conversion of fructose to fructose-1-phosphate. The product of this gene is the first enzyme with a specialized pathway that catabolizes dietary fructose. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 2-27087015-G-A is Benign according to our data. Variant chr2-27087015-G-A is described in ClinVar as [Benign]. Clinvar id is 335478.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 = 0.00773 (1178/152326) while in subpopulation SAS AF= 0.0211 (102/4830). AF 95% confidence interval is 0.0178. There are 8 homozygotes in gnomad4. There are 620 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KHK	NM_006488.3	c.-245G>A		5_prime_UTR_variant	1/8	ENST00000260598.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KHK	ENST00000260598.10	c.-245G>A		5_prime_UTR_variant	1/8	2	NM_006488.3	P3
KHK	ENST00000260599.11	c.-245G>A		5_prime_UTR_variant	1/8	1		A1
KHK	ENST00000429697.2	c.-245G>A		5_prime_UTR_variant	1/9	5
KHK	ENST00000490823.5	n.129+103G>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.00775 AC: 1180 AN: 152208 Hom.: 8 Cov.: 33

Gnomad AFR AF: 0.00186

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00811

Gnomad ASJ AF: 0.00548

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0215

Gnomad FIN AF: 0.0188

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00935

Gnomad OTH AF: 0.00860

GnomAD4 exome AF: 0.0103 AC: 2806 AN: 272228 Hom.: 34 Cov.: 0 AF XY: 0.0108 AC XY: 1525 AN XY: 140876

Gnomad4 AFR exome AF: 0.00187

Gnomad4 AMR exome AF: 0.00925

Gnomad4 ASJ exome AF: 0.00505

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0225

Gnomad4 FIN exome AF: 0.0168

Gnomad4 NFE exome AF: 0.0104

Gnomad4 OTH exome AF: 0.00917

GnomAD4 genome AF: 0.00773 AC: 1178 AN: 152326 Hom.: 8 Cov.: 33 AF XY: 0.00832 AC XY: 620 AN XY: 74500

Gnomad4 AFR AF: 0.00185

Gnomad4 AMR AF: 0.00804

Gnomad4 ASJ AF: 0.00548

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0211

Gnomad4 FIN AF: 0.0188

Gnomad4 NFE AF: 0.00937

Gnomad4 OTH AF: 0.00851

Alfa AF: 0.0107 Hom.: 3

Bravo AF: 0.00646

Asia WGS AF: 0.00751 AC: 26 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Essential fructosuria Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	7.2
DANN	Benign	0.70
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs192615638; hg19: chr2-27309883;