2-27086791-A-C

Position:

• chr2-27086791-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006488.3(KHK):​c.-469A>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.521 in 152,656 control chromosomes in the GnomAD database, including 22,537 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.52 (22447 hom., cov: 34)
  • Exomes 𝑓: 0.56 (90 hom.)
• Consequence: KHK NM_006488.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0440

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=-0.79).
• BP6: Variant 2-27086791-A-C is Benign according to our data. Variant chr2-27086791-A-C is described in ClinVar as [Benign]. Clinvar id is 335473.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.757 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KHK	NM_006488.3	c.-469A>C		5_prime_UTR_variant	1/8	ENST00000260598.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KHK	ENST00000260598.10	c.-469A>C		5_prime_UTR_variant	1/8	2	NM_006488.3	P3
KHK	ENST00000260599.11	c.-469A>C		5_prime_UTR_variant	1/8	1		A1
KHK	ENST00000490823.5	n.8A>C		non_coding_transcript_exon_variant	1/10	5
KHK	ENST00000429697.2			upstream_gene_variant		5

Frequencies

GnomAD3 genomes AF: 0.521 AC: 79186 AN: 152012 Hom.: 22445 Cov.: 34

Gnomad AFR AF: 0.301

Gnomad AMI AF: 0.469

Gnomad AMR AF: 0.443

Gnomad ASJ AF: 0.597

Gnomad EAS AF: 0.777

Gnomad SAS AF: 0.685

Gnomad FIN AF: 0.658

Gnomad MID AF: 0.624

Gnomad NFE AF: 0.616

Gnomad OTH AF: 0.546

GnomAD4 exome AF: 0.563 AC: 297 AN: 528 Hom.: 90 Cov.: 0 AF XY: 0.603 AC XY: 188 AN XY: 312

Gnomad4 AFR exome AF: 0.286

Gnomad4 AMR exome AF: 0.438

Gnomad4 ASJ exome AF: 0.600

Gnomad4 EAS exome AF: 0.667

Gnomad4 SAS exome AF: 0.614

Gnomad4 FIN exome AF: 0.500

Gnomad4 NFE exome AF: 0.542

Gnomad4 OTH exome AF: 0.615

GnomAD4 genome AF: 0.521 AC: 79194 AN: 152128 Hom.: 22447 Cov.: 34 AF XY: 0.525 AC XY: 39065 AN XY: 74386

Gnomad4 AFR AF: 0.300

Gnomad4 AMR AF: 0.442

Gnomad4 ASJ AF: 0.597

Gnomad4 EAS AF: 0.777

Gnomad4 SAS AF: 0.686

Gnomad4 FIN AF: 0.658

Gnomad4 NFE AF: 0.616

Gnomad4 OTH AF: 0.543

Alfa AF: 0.547 Hom.: 2965

Bravo AF: 0.489

Asia WGS AF: 0.672 AC: 2329 AN: 3466

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 13, 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	-0.79
CADD	Benign	12
DANN	Benign	0.58
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: rs6742004; hg19: chr2-27309659; COSMIC: COSV53157622; COSMIC: COSV53157622;