6-3012601-A-T

Position:

• chr6-3012601-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000904.6(NQO2):​c.230A>T​(p.Lys77Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: NQO2 NM_000904.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.87

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NQO2	NM_000904.6	c.230A>T	p.Lys77Met	missense_variant	4/7	ENST00000380455.11	NP_000895.2
NQO2	NM_001290221.2	c.230A>T	p.Lys77Met	missense_variant	7/10		NP_001277150.1
NQO2	NM_001318940.2	c.230A>T	p.Lys77Met	missense_variant	4/7		NP_001305869.1
NQO2	NM_001290222.2	c.230A>T	p.Lys77Met	missense_variant	4/6		NP_001277151.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NQO2	ENST00000380455.11	c.230A>T	p.Lys77Met	missense_variant	4/7	1	NM_000904.6	ENSP00000369822	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 19, 2024

The c.230A>T (p.K77M) alteration is located in exon 4 (coding exon 3) of the NQO2 gene. This alteration results from a A to T substitution at nucleotide position 230, causing the lysine (K) at amino acid position 77 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	.;.;T;.;T;.;T
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.76	.;T;.;.;.;T;T
M_CAP	Benign	0.016	T
MetaRNN	Uncertain	0.45	T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.7	.;.;M;.;M;.;M
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Benign	0.35	T
PROVEAN	Pathogenic	-4.7	D;D;D;D;D;D;D
REVEL	Benign	0.16
Sift	Uncertain	0.018	D;D;D;D;D;D;D
Sift4G	Uncertain	0.015	D;D;D;D;D;D;D
Polyphen		0.35	.;.;B;.;B;.;B
Vest4		0.27, 0.26, 0.38
MutPred		0.50		Loss of loop (P = 0.0128);Loss of loop (P = 0.0128);Loss of loop (P = 0.0128);Loss of loop (P = 0.0128);Loss of loop (P = 0.0128);Loss of loop (P = 0.0128);Loss of loop (P = 0.0128);
MVP		0.41
MPC		0.50
ClinPred		0.99	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.62
gMVP		0.71

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-3012835;