rs74537742

chr2-27094472-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The ENST00000260599.11(KHK):c.210-5A>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0105 in 1,613,080 control chromosomes in the GnomAD database, including 1,521 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.057 (833 hom., cov: 33)
  • Exomes 𝑓: 0.0056 (688 hom.)
• Consequence: KHK ENST00000260599.11 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.001299
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.35

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 2-27094472-A-G is Benign according to our data. Variant chr2-27094472-A-G is described in ClinVar as [Benign]. Clinvar id is 335485.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.195 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KHK	NM_006488.3	c.210-328A>G		intron_variant		ENST00000260598.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KHK	ENST00000260598.10	c.210-328A>G		intron_variant		2	NM_006488.3	P3

Frequencies

GnomAD3 genomes AF: 0.0571 AC: 8677 AN: 151952 Hom.: 828 Cov.: 33

Gnomad AFR AF: 0.198

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0221

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000485

Gnomad OTH AF: 0.0455

GnomAD3 exomes AF: 0.0145 AC: 3645 AN: 251086 Hom.: 315 AF XY: 0.0103 AC XY: 1394 AN XY: 135720

Gnomad AFR exome AF: 0.200

Gnomad AMR exome AF: 0.00882

Gnomad ASJ exome AF: 0.000497

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000299

Gnomad OTH exome AF: 0.00798

GnomAD4 exome AF: 0.00563 AC: 8223 AN: 1461010 Hom.: 688 Cov.: 32 AF XY: 0.00476 AC XY: 3458 AN XY: 726832

Gnomad4 AFR exome AF: 0.199

Gnomad4 AMR exome AF: 0.0110

Gnomad4 ASJ exome AF: 0.000459

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000487

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000164

Gnomad4 OTH exome AF: 0.0127

GnomAD4 genome AF: 0.0573 AC: 8712 AN: 152070 Hom.: 833 Cov.: 33 AF XY: 0.0545 AC XY: 4052 AN XY: 74322

Gnomad4 AFR AF: 0.199

Gnomad4 AMR AF: 0.0221

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000485

Gnomad4 OTH AF: 0.0450

Alfa AF: 0.0272 Hom.: 187

Bravo AF: 0.0658

Asia WGS AF: 0.00895 AC: 31 AN: 3478

EpiCase AF: 0.000654

EpiControl AF: 0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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	-0.49
Cadd	Benign	17
Dann	Benign	0.84

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0013
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: rs74537742; hg19: chr2-27317340;