Genetic Variant NQO2:p.Leu7Phe (chr6-3010036-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000904.6(NQO2):c.19C>T(p.Leu7Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000682 in 1,612,144 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L7P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000070 ( 1 hom. )

Consequence

NQO2
NM_000904.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.730

Publications

2 publications found

Variant links:

Genes affected

NQO2 (HGNC:7856): (N-ribosyldihydronicotinamide:quinone dehydrogenase 2) This gene encodes a member of the thioredoxin family of enzymes. It is a cytosolic and ubiquitously expressed flavoprotein that catalyzes the two-electron reduction of quinone substrates and uses dihydronicotinamide riboside as a reducing coenzyme. Mutations in this gene have been associated with neurodegenerative diseases and several cancers. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2014]

NQO2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000904.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NQO2	NM_000904.6	MANE Select	c.19C>T	p.Leu7Phe	missense	Exon 3 of 7	NP_000895.2	P16083
NQO2	NM_001290221.2		c.19C>T	p.Leu7Phe	missense	Exon 6 of 10	NP_001277150.1	P16083
NQO2	NM_001318940.2		c.19C>T	p.Leu7Phe	missense	Exon 3 of 7	NP_001305869.1	P16083

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NQO2	ENST00000380455.11	TSL:1 MANE Select	c.19C>T	p.Leu7Phe	missense	Exon 3 of 7	ENSP00000369822.4	P16083
NQO2	ENST00000952452.1		c.64C>T	p.Leu22Phe	missense	Exon 3 of 7	ENSP00000622511.1
NQO2	ENST00000338130.7	TSL:2	c.19C>T	p.Leu7Phe	missense	Exon 6 of 10	ENSP00000337773.2	P16083

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152076

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000103

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000400

AC:

AN:

249812

AF XY:

0.0000444

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000295

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000795

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000699

AC:

102

AN:

1460068

Hom.:

Cov.:

AF XY:

0.0000743

AC XY:

AN XY:

726350

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33398

American (AMR)

AF:

0.0000227

AC:

AN:

44104

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26026

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.00

AC:

AN:

86030

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53388

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.0000855

AC:

AN:

1111358

Other (OTH)

AF:

0.0000995

AC:

AN:

60320

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.446

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

AF:

0.0000526

AC:

AN:

152076

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74294

show subpopulations

African (AFR)

AF:

0.0000242

AC:

AN:

41406

American (AMR)

AF:

0.00

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10582

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

68000

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000115

Hom.:

Bravo

AF:

0.0000604

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.0000547

EpiControl

AF:

0.00

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Uncertain

0.081

BayesDel_noAF

Uncertain

0.070

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.31

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Benign

0.56

LIST_S2

Pathogenic

0.99

M_CAP

Benign

0.053

MetaRNN

Uncertain

0.56

MetaSVM

Benign

-0.80

MutationAssessor

Pathogenic

3.0

PhyloP100

0.73

PrimateAI

Uncertain

0.78

PROVEAN

Uncertain

-3.7

REVEL

Uncertain

0.34

Sift

Uncertain

0.026

Sift4G

Uncertain

0.038

Polyphen

1.0

Vest4

0.52

MVP

0.28

MPC

0.29

ClinPred

0.88

GERP RS

4.7

Varity_R

0.81

gMVP

0.62

Mutation Taster

=61/39

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

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