Genetic Variant NEIL2:p.Arg257Leu (chr8-11786044-G-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_145043.4(NEIL2):c.770G>T(p.Arg257Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0218 in 1,614,080 control chromosomes in the GnomAD database, including 1,531 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.023 ( 157 hom., cov: 32)

Exomes 𝑓: 0.022 ( 1374 hom. )

Consequence

NEIL2
NM_145043.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.90

Publications

32 publications found

Variant links:

Genes affected

NEIL2 (HGNC:18956): (nei like DNA glycosylase 2) This gene encodes a member of the Fpg/Nei family of DNA glycosylases. These glycosylases initiate the first step in base excision repair by cleaving oxidatively damaged bases and introducing a DNA strand break via their abasic site lyase activity. This enzyme is primarily associated with DNA repair during transcription and acts prefentially on cytosine-derived lesions, particularly 5-hydroxyuracil and 5-hydroxycytosine. It contains an N-terminal catalytic domain, a hinge region, and a C-terminal DNA-binding domain with helix-two-turn-helix and zinc finger motifs. This enzyme interacts with the X-ray cross complementing factor 1 scaffold protein as part of a multi-protein DNA repair complex. A pseudogene of this gene has been identified. [provided by RefSeq, Mar 2017]

NEIL2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0047496855).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.21 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_145043.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NEIL2	NM_145043.4	MANE Select	c.770G>T	p.Arg257Leu	missense	Exon 5 of 5	NP_659480.1	Q969S2-1
NEIL2	NM_001135746.3		c.770G>T	p.Arg257Leu	missense	Exon 5 of 5	NP_001129218.1	Q969S2-1
NEIL2	NM_001349442.2		c.770G>T	p.Arg257Leu	missense	Exon 6 of 6	NP_001336371.1	Q969S2-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NEIL2	ENST00000284503.7	TSL:2 MANE Select	c.770G>T	p.Arg257Leu	missense	Exon 5 of 5	ENSP00000284503.6	Q969S2-1
NEIL2	ENST00000436750.7	TSL:1	c.770G>T	p.Arg257Leu	missense	Exon 5 of 5	ENSP00000394023.2	Q969S2-1
NEIL2	ENST00000455213.6	TSL:5	c.770G>T	p.Arg257Leu	missense	Exon 6 of 6	ENSP00000397538.2	Q969S2-1

Frequencies

GnomAD3 genomes

AF:

0.0227

AC:

3452

AN:

152114

Hom.:

158

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00449

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0202

Gnomad ASJ

AF:

0.00519

Gnomad EAS

AF:

0.222

Gnomad SAS

AF:

0.0116

Gnomad FIN

AF:

0.0774

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0130

Gnomad OTH

AF:

0.0143

GnomAD2 exomes

AF:

0.0381

AC:

9580

AN:

251478

AF XY:

0.0355

show subpopulations

Gnomad AFR exome

AF:

0.00351

Gnomad AMR exome

AF:

0.0424

Gnomad ASJ exome

AF:

0.00476

Gnomad EAS exome

AF:

0.224

Gnomad FIN exome

AF:

0.0777

Gnomad NFE exome

AF:

0.0160

Gnomad OTH exome

AF:

0.0300

GnomAD4 exome

AF:

0.0217

AC:

31712

AN:

1461848

Hom.:

1374

Cov.:

AF XY:

0.0211

AC XY:

15334

AN XY:

727224

show subpopulations

African (AFR)

AF:

0.00251

AC:

AN:

33480

American (AMR)

AF:

0.0409

AC:

1827

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00608

AC:

159

AN:

26136

East Asian (EAS)

AF:

0.224

AC:

8886

AN:

39700

South Asian (SAS)

AF:

0.00719

AC:

620

AN:

86256

European-Finnish (FIN)

AF:

0.0756

AC:

4036

AN:

53418

Middle Eastern (MID)

AF:

0.00243

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0132

AC:

14709

AN:

1111976

Other (OTH)

AF:

0.0228

AC:

1377

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

1884

3768

5653

7537

9421

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

664

1328

1992

2656

3320

<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:

0.0227

AC:

3449

AN:

152232

Hom.:

157

Cov.:

AF XY:

0.0263

AC XY:

1958

AN XY:

74438

show subpopulations

African (AFR)

AF:

0.00448

AC:

186

AN:

41544

American (AMR)

AF:

0.0203

AC:

311

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00519

AC:

AN:

3470

East Asian (EAS)

AF:

0.221

AC:

1142

AN:

5168

South Asian (SAS)

AF:

0.0114

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0774

AC:

821

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0130

AC:

885

AN:

68006

Other (OTH)

AF:

0.0147

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

175

351

526

702

877

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

144

192

240

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0192

Hom.:

445

Bravo

AF:

0.0199

TwinsUK

AF:

0.0151

AC:

ALSPAC

AF:

0.0174

AC:

ESP6500AA

AF:

0.00431

AC:

ESP6500EA

AF:

0.0123

AC:

106

ExAC

AF:

0.0364

AC:

4421

Asia WGS

AF:

0.0760

AC:

264

AN:

3478

EpiCase

AF:

0.0108

EpiControl

AF:

0.0112

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.77

BayesDel_noAF

Benign

-0.73

CADD

Benign

2.7

(source)

DANN

Benign

0.53

DEOGEN2

Benign

0.014

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.025

LIST_S2

Benign

0.76

MetaRNN

Benign

0.0047

MetaSVM

Benign

-0.92

MutationAssessor

Benign

-2.0

PhyloP100

1.9

PrimateAI

Benign

0.34

PROVEAN

Benign

4.7

REVEL

Benign

0.042

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0010

Vest4

0.071

MPC

0.0036

ClinPred

0.0030

GERP RS

3.0

Varity_R

0.062

gMVP

0.40

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over