2-27092428-G-A

Position:

chr2-27092428-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_006488.3(KHK):c.189G>A(p.Met63Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000185 in 1,613,200 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0011 ( 3 hom., cov: 33)

Exomes 𝑓: 0.000090 ( 0 hom. )

Consequence

KHK
NM_006488.3 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 2.84

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 Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011464).

BP6

Variant 2-27092428-G-A is Benign according to our data. Variant chr2-27092428-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 896717.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KHK	NM_006488.3 linkuse as main transcript	c.189G>A	p.Met63Ile	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.189G>A	p.Met63Ile	missense_variant	2/8	2	NM_006488.3	ENSP00000260598	P3	P50053-1
KHK	ENST00000260599.11 linkuse as main transcript	c.189G>A	p.Met63Ile	missense_variant	2/8	1		ENSP00000260599	A1	P50053-2
KHK	ENST00000429697.2 linkuse as main transcript	c.189G>A	p.Met63Ile	missense_variant	2/9	5		ENSP00000404741
KHK	ENST00000490823.5 linkuse as main transcript	n.537G>A		non_coding_transcript_exon_variant	4/10	5

Frequencies

GnomAD3 genomes

AF:

0.00103

AC:

157

AN:

152242

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00338

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00111

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000312

AC:

AN:

249982

Hom.:

AF XY:

0.000236

AC XY:

AN XY:

135326

show subpopulations

Gnomad AFR exome

AF:

0.00359

Gnomad AMR exome

AF:

0.000493

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000884

Gnomad OTH exome

AF:

0.000327

GnomAD4 exome

AF:

0.0000904

AC:

132

AN:

1460840

Hom.:

Cov.:

AF XY:

0.0000798

AC XY:

AN XY:

726756

show subpopulations

Gnomad4 AFR exome

AF:

0.00284

Gnomad4 AMR exome

AF:

0.000425

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.000232

GnomAD4 genome

AF:

0.00110

AC:

167

AN:

152360

Hom.:

Cov.:

AF XY:

0.00105

AC XY:

AN XY:

74504

show subpopulations

Gnomad4 AFR

AF:

0.00361

Gnomad4 AMR

AF:

0.00111

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000201

Hom.:

Bravo

AF:

0.00120

ESP6500AA

AF:

0.00409

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000379

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Essential fructosuria

Benign:1

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.44

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.33

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.28

.;T;T

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.12

FATHMM_MKL

Uncertain

0.82

LIST_S2

Uncertain

0.88

D;D;D

M_CAP

Benign

0.052

MetaRNN

Benign

0.011

T;T;T

MetaSVM

Benign

-0.83

MutationAssessor

Benign

-0.080

N;N;.

MutationTaster

Benign

0.93

D;D

PrimateAI

Uncertain

0.48

PROVEAN

Benign

0.12

N;N;N

REVEL

Benign

0.14

Sift

Uncertain

0.018

D;D;D

Sift4G

Benign

0.10

T;T;D

Polyphen

0.0

B;B;.

Vest4

0.31

MutPred

0.47

Gain of catalytic residue at P65 (P = 0.0305);Gain of catalytic residue at P65 (P = 0.0305);Gain of catalytic residue at P65 (P = 0.0305);

MVP

0.68

MPC

0.21

ClinPred

0.024

GERP RS

4.8

Varity_R

0.29

gMVP

0.22

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