chr2-27099556-G-A

Position:

chr2-27099556-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_006488.3(KHK):c.790G>A(p.Val264Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00166 in 1,614,144 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0015 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0017 ( 4 hom. )

Consequence

KHK
NM_006488.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 6.44

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:

CGREF1 (HGNC:16962): (cell growth regulator with EF-hand domain 1) Predicted to enable calcium ion binding activity. Predicted to be involved in negative regulation of cell population proliferation. Predicted to be located in extracellular region. [provided by Alliance of Genome Resources, Apr 2022]

CGREF1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.016144037).

BP6

Variant 2-27099556-G-A is Benign according to our data. Variant chr2-27099556-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 335497.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

BS2

High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KHK	NM_006488.3 linkuse as main transcript	c.790G>A	p.Val264Ile	missense_variant	7/8	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.790G>A	p.Val264Ile	missense_variant	7/8	2	NM_006488.3	ENSP00000260598	P3	P50053-1

Frequencies

GnomAD3 genomes

AF:

0.00150

AC:

229

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000531

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00452

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00193

Gnomad OTH

AF:

0.00288

GnomAD3 exomes

AF:

0.00121

AC:

304

AN:

251246

Hom.:

AF XY:

0.00121

AC XY:

165

AN XY:

135812

show subpopulations

Gnomad AFR exome

AF:

0.000492

Gnomad AMR exome

AF:

0.00289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00156

Gnomad OTH exome

AF:

0.00228

GnomAD4 exome

AF:

0.00167

AC:

2446

AN:

1461856

Hom.:

Cov.:

AF XY:

0.00163

AC XY:

1187

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.000508

Gnomad4 AMR exome

AF:

0.00266

Gnomad4 ASJ exome

AF:

0.000115

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.000151

Gnomad4 FIN exome

AF:

0.0000749

Gnomad4 NFE exome

AF:

0.00196

Gnomad4 OTH exome

AF:

0.00179

GnomAD4 genome

AF:

0.00150

AC:

229

AN:

152288

Hom.:

Cov.:

AF XY:

0.00148

AC XY:

110

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.000529

Gnomad4 AMR

AF:

0.00451

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000943

Gnomad4 NFE

AF:

0.00193

Gnomad4 OTH

AF:

0.00285

Alfa

AF:

0.00162

Hom.:

Bravo

AF:

0.00160

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00259

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00140

AC:

ExAC

AF:

0.00103

AC:

125

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00142

EpiControl

AF:

0.00148

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Essential fructosuria

Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 08, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.11

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.29

.;T

Eigen

Benign

-0.31

Eigen_PC

Benign

-0.15

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.83

T;T

M_CAP

Benign

0.051

MetaRNN

Benign

0.016

T;T

MetaSVM

Benign

-0.77

MutationAssessor

Uncertain

2.2

M;M

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-0.29

N;N

REVEL

Uncertain

0.36

Sift

Benign

0.16

T;T

Sift4G

Benign

0.45

T;T

Polyphen

0.0070

B;B

Vest4

0.46

MVP

0.53

MPC

0.15

ClinPred

0.049

GERP RS

3.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.11

gMVP

0.69

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

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