Variant 2-27092357-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5

The NM_006488.3(KHK):c.118G>A(p.Gly40Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000215 in 1,613,320 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: 𝑓 0.00024 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00021 ( 1 hom. )

Consequence

KHK
NM_006488.3 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 9.13

Variant links:

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]

KHK links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.945

PP5

Variant 2-27092357-G-A is Pathogenic according to our data. Variant chr2-27092357-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 12031.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KHK	NM_006488.3 linkuse as main transcript	c.118G>A	p.Gly40Arg	missense_variant	2/8	ENST00000260598.10	NP_006479.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KHK	ENST00000260598.10 linkuse as main transcript	c.118G>A	p.Gly40Arg	missense_variant	2/8	2	NM_006488.3	ENSP00000260598	P3	P50053-1
KHK	ENST00000260599.11 linkuse as main transcript	c.118G>A	p.Gly40Arg	missense_variant	2/8	1		ENSP00000260599	A1	P50053-2
KHK	ENST00000429697.2 linkuse as main transcript	c.118G>A	p.Gly40Arg	missense_variant	2/9	5		ENSP00000404741
KHK	ENST00000490823.5 linkuse as main transcript	n.466G>A		non_coding_transcript_exon_variant	4/10	5

Frequencies

GnomAD3 genomes

AF:

0.000243

AC:

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000850

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000265

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000140

AC:

AN:

250840

Hom.:

AF XY:

0.000162

AC XY:

AN XY:

135696

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000218

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000229

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000212

AC:

310

AN:

1460982

Hom.:

Cov.:

AF XY:

0.000201

AC XY:

146

AN XY:

726842

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000894

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000258

Gnomad4 OTH exome

AF:

0.000182

GnomAD4 genome

AF:

0.000243

AC:

AN:

152338

Hom.:

Cov.:

AF XY:

0.000201

AC XY:

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.0000962

Gnomad4 AMR

AF:

0.000849

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000265

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000176

Hom.:

Bravo

AF:

0.000276

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000988

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000356

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Essential fructosuria

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 01, 1994

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.48

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.86

.;D;D

Eigen

Pathogenic

0.90

Eigen_PC

Pathogenic

0.81

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.97

D;D;D

M_CAP

Pathogenic

0.50

MetaRNN

Pathogenic

0.95

D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.5

M;M;.

MutationTaster

Benign

1.0

A;A

PrimateAI

Uncertain

0.76

PROVEAN

Pathogenic

-7.1

D;D;D

REVEL

Pathogenic

0.95

Sift

Uncertain

0.0020

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;D;.

Vest4

0.98

MutPred

0.93

Gain of solvent accessibility (P = 2e-04);Gain of solvent accessibility (P = 2e-04);Gain of solvent accessibility (P = 2e-04);

MVP

0.99

MPC

0.81

ClinPred

0.84

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.98

gMVP

0.89

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over