Genetic Variant KHK:p.Val49Leu (chr2-27092384-G-C) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_006488.3(KHK):c.145G>C(p.Val49Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,182 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V49I) has been classified as Benign.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

KHK
NM_006488.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.25

Publications

44 publications found

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 Gene-Disease associations (from GenCC):

essential fructosuria
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

KHK links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.791

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006488.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KHK	NM_006488.3	MANE Select	c.145G>C	p.Val49Leu	missense	Exon 2 of 8	NP_006479.1	P50053-1
	KHK	NM_000221.3		c.145G>C	p.Val49Leu	missense	Exon 2 of 8	NP_000212.1	P50053-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KHK	ENST00000260598.10	TSL:2 MANE Select	c.145G>C	p.Val49Leu	missense	Exon 2 of 8	ENSP00000260598.5	P50053-1
KHK	ENST00000260599.11	TSL:1	c.145G>C	p.Val49Leu	missense	Exon 2 of 8	ENSP00000260599.6	P50053-2
KHK	ENST00000908283.1		c.145G>C	p.Val49Leu	missense	Exon 2 of 9	ENSP00000578342.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461182

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726934

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52780

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111962

Other (OTH)

AF:

0.00

AC:

AN:

60388

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

32268

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.87

BayesDel_addAF

Uncertain

0.080

BayesDel_noAF

Benign

-0.12

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.68

Eigen

Benign

-0.11

Eigen_PC

Benign

-0.11

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.94

M_CAP

Uncertain

0.11

MetaRNN

Pathogenic

0.79

MetaSVM

Uncertain

-0.085

MutationAssessor

Pathogenic

3.4

PhyloP100

4.2

PrimateAI

Uncertain

0.68

PROVEAN

Uncertain

-2.7

REVEL

Uncertain

0.44

Sift

Benign

0.040

Sift4G

Uncertain

0.0070

Polyphen

0.33

Vest4

0.53

MutPred

0.64

Loss of catalytic residue at V49 (P = 0.136)

MVP

0.74

MPC

0.66

ClinPred

0.98

GERP RS

2.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.67

gMVP

0.62

Mutation Taster

=79/21

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over