NM_000015.3:c.406G>C

Variant names:

• chr8-18400409-G-C
• NM_000015.3:c.406G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000015.3(NAT2):​c.406G>C​(p.Glu136Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,459,946 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: NAT2 NM_000015.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.33
• Publications: 0 publications found

Genes affected

NAT2 (HGNC:7646): (N-acetyltransferase 2) This gene encodes an enzyme that functions to both activate and deactivate arylamine and hydrazine drugs and carcinogens. Polymorphisms in this gene are responsible for the N-acetylation polymorphism in which human populations segregate into rapid, intermediate, and slow acetylator phenotypes. Polymorphisms in this gene are also associated with higher incidences of cancer and drug toxicity. A second polymorphic arylamine N-acetyltransferase gene (NAT1), is located near this gene (NAT2). [provided by RefSeq, Sep 2019]

ACMG classification

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, 0.75

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000015.3. 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
	NAT2	NM_000015.3	MANE Select	c.406G>C	p.Glu136Gln	missense	Exon 2 of 2	NP_000006.2	P11245

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NAT2	ENST00000286479.4	TSL:1 MANE Select	c.406G>C	p.Glu136Gln	missense	Exon 2 of 2	ENSP00000286479.3	P11245
	NAT2	ENST00000893781.1		c.406G>C	p.Glu136Gln	missense	Exon 3 of 3	ENSP00000563840.1
	NAT2	ENST00000893782.1		c.406G>C	p.Glu136Gln	missense	Exon 3 of 3	ENSP00000563841.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459946 Hom.: 0 Cov.: 57 AF XY: 0.00 AC XY: 0 AN XY: 726232

African (AFR) AF: 0.00 AC: 0 AN: 33332

American (AMR) AF: 0.00 AC: 0 AN: 44358

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25916

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 85846

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53370

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5742

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111396

Other (OTH) AF: 0.00 AC: 0 AN: 60290

GnomAD4 genome Cov.: 30

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.074	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.014	T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.0081	T
MetaRNN	Pathogenic	0.75	D
MetaSVM	Benign	-1.2	T
PhyloP100		4.3
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.29
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.039	D
Polyphen		1.0	D
Vest4		0.45
MutPred		0.47		Loss of ubiquitination at K141 (P = 0.0787)
MVP		0.76
MPC		0.021
ClinPred		0.99	D
GERP RS		3.0
gMVP		0.55
Mutation Taster		=55/45	polymorphism

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

Other links and lift over

hg19: chr8-18257919;