dbSNP rs1208: NAT2:p.Arg268Lys (chr8-18400806-G-A) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The ENST00000520116.1(NAT2):c.413G>A(p.Arg138Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.592 in 1,610,782 control chromosomes in the GnomAD database, including 286,455 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

Frequency

Genomes: 𝑓 0.60 ( 28055 hom., cov: 31)

Exomes 𝑓: 0.59 ( 258400 hom. )

Consequence

NAT2
ENST00000520116.1 missense

Scores

Clinical Significance

Likely benign no assertion criteria provided B:1

Conservation

PhyloP100: 0.0830

Variant links:

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]

NAT2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=6.8380643E-7).

BP6

Variant 8-18400806-G-A is Benign according to our data. Variant chr8-18400806-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3059207.Status of the report is no_assertion_criteria_provided, 0 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.938 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NAT2	NM_000015.3 link	c.803G>A	p.Arg268Lys	missense_variant	Exon 2 of 2	ENST00000286479.4	NP_000006.2	P11245A4Z6T7
NAT2	XM_017012938.2 link	c.803G>A	p.Arg268Lys	missense_variant	Exon 3 of 3		XP_016868427.1	P11245A4Z6T7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NAT2	ENST00000286479.4 link	c.803G>A	p.Arg268Lys	missense_variant	Exon 2 of 2	1	NM_000015.3	ENSP00000286479.3		P11245
NAT2	ENST00000520116.1 link	c.413G>A	p.Arg138Lys	missense_variant	Exon 2 of 2	3		ENSP00000428416.1		E7EWF9

Frequencies

GnomAD3 genomes

AF:

0.602

AC:

91371

AN:

151750

Hom.:

28047

Cov.:

show subpopulations

Gnomad AFR

AF:

0.601

Gnomad AMI

AF:

0.677

Gnomad AMR

AF:

0.635

Gnomad ASJ

AF:

0.559

Gnomad EAS

AF:

0.960

Gnomad SAS

AF:

0.650

Gnomad FIN

AF:

0.553

Gnomad MID

AF:

0.538

Gnomad NFE

AF:

0.574

Gnomad OTH

AF:

0.594

GnomAD3 exomes

AF:

0.619

AC:

153259

AN:

247584

Hom.:

48818

AF XY:

0.617

AC XY:

82695

AN XY:

134048

show subpopulations

Gnomad AFR exome

AF:

0.597

Gnomad AMR exome

AF:

0.657

Gnomad ASJ exome

AF:

0.558

Gnomad EAS exome

AF:

0.959

Gnomad SAS exome

AF:

0.645

Gnomad FIN exome

AF:

0.558

Gnomad NFE exome

AF:

0.567

Gnomad OTH exome

AF:

0.587

GnomAD4 exome

AF:

0.591

AC:

862387

AN:

1458914

Hom.:

258400

Cov.:

AF XY:

0.592

AC XY:

429292

AN XY:

725744

show subpopulations

Gnomad4 AFR exome

AF:

0.595

Gnomad4 AMR exome

AF:

0.655

Gnomad4 ASJ exome

AF:

0.565

Gnomad4 EAS exome

AF:

0.965

Gnomad4 SAS exome

AF:

0.646

Gnomad4 FIN exome

AF:

0.563

Gnomad4 NFE exome

AF:

0.573

Gnomad4 OTH exome

AF:

0.600

GnomAD4 genome

AF:

0.602

AC:

91412

AN:

151868

Hom.:

28055

Cov.:

AF XY:

0.604

AC XY:

44838

AN XY:

74208

show subpopulations

Gnomad4 AFR

AF:

0.600

Gnomad4 AMR

AF:

0.635

Gnomad4 ASJ

AF:

0.559

Gnomad4 EAS

AF:

0.960

Gnomad4 SAS

AF:

0.649

Gnomad4 FIN

AF:

0.553

Gnomad4 NFE

AF:

0.574

Gnomad4 OTH

AF:

0.598

Alfa

AF:

0.575

Hom.:

41260

Bravo

AF:

0.607

TwinsUK

AF:

0.572

AC:

2120

ALSPAC

AF:

0.581

AC:

2238

ESP6500AA

AF:

0.601

AC:

2646

ESP6500EA

AF:

0.576

AC:

4951

ExAC

AF:

0.615

AC:

74582

Asia WGS

AF:

0.779

AC:

2709

AN:

3478

EpiCase

AF:

0.570

EpiControl

AF:

0.572

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

NAT2-related disorder

Benign:1

Nov 06, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.84

BayesDel_noAF

Benign

-0.83

CADD

Benign

1.3

DANN

Benign

0.24

DEOGEN2

Benign

0.0040

.;T

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.0028

LIST_S2

Benign

0.035

T;T

MetaRNN

Benign

6.8e-7

T;T

MetaSVM

Benign

-1.0

PrimateAI

Benign

0.35

PROVEAN

Benign

1.4

N;N

REVEL

Benign

0.041

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0

B;.

Vest4

0.013

MPC

0.0046

ClinPred

0.000022

GERP RS

1.5

gMVP

0.47

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over