Genetic Variant NFE2L2:c.184-31074A>G (chr2-177265345-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The ENST00000699346.1(NFE2L2):c.184-31074A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.314 in 199,732 control chromosomes in the GnomAD database, including 10,828 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.30 ( 7562 hom., cov: 33)

Exomes 𝑓: 0.36 ( 3266 hom. )

Consequence

NFE2L2
ENST00000699346.1 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.96

Publications

90 publications found

Variant links:

COSMIC-nc: COSV67961672

Genes affected

NFE2L2 (HGNC:7782): (NFE2 like bZIP transcription factor 2) This gene encodes a transcription factor which is a member of a small family of basic leucine zipper (bZIP) proteins. The encoded transcription factor regulates genes which contain antioxidant response elements (ARE) in their promoters; many of these genes encode proteins involved in response to injury and inflammation which includes the production of free radicals. Multiple transcript variants encoding different isoforms have been characterized for this gene. [provided by RefSeq, Sep 2015]

NFE2L2 Gene-Disease associations (from GenCC):

immunodeficiency, developmental delay, and hypohomocysteinemia
Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Illumina, G2P

NFE2L2 links:

ENSG00000222043 (HGNC:):

ENSG00000222043 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 (BayesDel_noAF=-0.61).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.505 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	Protein	UniProt
NFE2L2	ENST00000699346.1 link	c.184-31074A>G	intron_variant	Intron 7 of 10		ENSP00000514321.1	A0A8V8TNM0
NFE2L2	ENST00000586532.6 link	c.43-31074A>G	intron_variant	Intron 3 of 6	5	ENSP00000464920.2	K7EIW5
NFE2L2	ENST00000699265.1 link	c.43-31074A>G	intron_variant	Intron 5 of 8		ENSP00000514246.1	K7EIW5

Frequencies

GnomAD3 genomes

AF:

0.300

AC:

45585

AN:

152010

Hom.:

7543

Cov.:

show subpopulations

Gnomad AFR

AF:

0.180

Gnomad AMI

AF:

0.204

Gnomad AMR

AF:

0.400

Gnomad ASJ

AF:

0.254

Gnomad EAS

AF:

0.521

Gnomad SAS

AF:

0.492

Gnomad FIN

AF:

0.356

Gnomad MID

AF:

0.301

Gnomad NFE

AF:

0.315

Gnomad OTH

AF:

0.287

GnomAD4 exome

AF:

0.359

AC:

17104

AN:

47604

Hom.:

3266

Cov.:

AF XY:

0.359

AC XY:

7978

AN XY:

22232

show subpopulations

African (AFR)

AF:

0.189

AC:

373

AN:

1970

American (AMR)

AF:

0.425

AC:

536

AN:

1262

Ashkenazi Jewish (ASJ)

AF:

0.258

AC:

755

AN:

2930

East Asian (EAS)

AF:

0.570

AC:

4532

AN:

7956

South Asian (SAS)

AF:

0.551

AC:

239

AN:

434

European-Finnish (FIN)

AF:

0.367

AC:

AN:

128

Middle Eastern (MID)

AF:

0.280

AC:

AN:

282

European-Non Finnish (NFE)

AF:

0.323

AC:

9273

AN:

28746

Other (OTH)

AF:

0.326

AC:

1270

AN:

3896

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

515

1029

1544

2058

2573

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

136

204

272

340

<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:

0.300

AC:

45620

AN:

152128

Hom.:

7562

Cov.:

AF XY:

0.310

AC XY:

23043

AN XY:

74354

show subpopulations

African (AFR)

AF:

0.180

AC:

7468

AN:

41510

American (AMR)

AF:

0.401

AC:

6123

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.254

AC:

881

AN:

3468

East Asian (EAS)

AF:

0.521

AC:

2687

AN:

5154

South Asian (SAS)

AF:

0.492

AC:

2373

AN:

4824

European-Finnish (FIN)

AF:

0.356

AC:

3769

AN:

10580

Middle Eastern (MID)

AF:

0.299

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.315

AC:

21429

AN:

67992

Other (OTH)

AF:

0.292

AC:

616

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1692

3383

5075

6766

8458

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

472

944

1416

1888

2360

<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:

0.258

Hom.:

1184

Bravo

AF:

0.292

Asia WGS

AF:

0.528

AC:

1839

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.61

CADD

Benign

(source)

DANN

Benign

0.65

PhyloP100

2.0

Mutation Taster

=98/2

polymorphism (auto)

(source)

Splicing

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over