chr8-18400061-G-C

Variant names:

• chr8-18400061-G-C
• NM_000015.3:c.58G>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000015.3(NAT2):​c.58G>C​(p.Asp20His) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,402 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.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: NAT2 NM_000015.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.23

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

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.874

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NAT2	NM_000015.3	c.58G>C	p.Asp20His	missense_variant	Exon 2 of 2	ENST00000286479.4	NP_000006.2
NAT2	XM_017012938.2	c.58G>C	p.Asp20His	missense_variant	Exon 3 of 3		XP_016868427.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NAT2	ENST00000286479.4	c.58G>C	p.Asp20His	missense_variant	Exon 2 of 2	1	NM_000015.3	ENSP00000286479.3
NAT2	ENST00000520116.1	c.-57-276G>C		intron_variant	Intron 1 of 1	3		ENSP00000428416.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460402 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726328

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Uncertain	0.021	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	24
DANN	Uncertain	0.99
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.018	T
MetaRNN	Pathogenic	0.87	D
MetaSVM	Benign	-1.2	T
PrimateAI	Benign	0.47	T
PROVEAN	Pathogenic	-5.6	D
REVEL	Benign	0.26
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.77
MutPred		0.69		Gain of methylation at K18 (P = 0.0415);
MVP		0.66
MPC		0.019
ClinPred		0.99	D
GERP RS		3.0
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: chr8-18257571;