chr2-177238501-A-G

Variant names:

• chr2-177238501-A-G
• rs6726395
• NM_006164.5:c.46-4230T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006164.5(NFE2L2):​c.46-4230T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.524 in 152,066 control chromosomes in the GnomAD database, including 21,391 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 0.52 (21391 hom., cov: 33)
• Consequence: NFE2L2 NM_006164.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.164
• Publications: 51 publications found

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.721 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006164.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NFE2L2	NM_006164.5	MANE Select	c.46-4230T>C		intron	N/A	NP_006155.2
	NFE2L2	NM_001145412.3		c.-3-4230T>C		intron	N/A	NP_001138884.1
	NFE2L2	NM_001313900.1		c.-3-4230T>C		intron	N/A	NP_001300829.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NFE2L2	ENST00000397062.8	TSL:1 MANE Select	c.46-4230T>C		intron	N/A	ENSP00000380252.3
	NFE2L2	ENST00000397063.9	TSL:1	c.-3-4230T>C		intron	N/A	ENSP00000380253.4
	NFE2L2	ENST00000421929.6	TSL:1	c.-3-4230T>C		intron	N/A	ENSP00000412191.2

Frequencies

GnomAD3 genomes AF: 0.524 AC: 79616 AN: 151948 Hom.: 21374 Cov.: 33

Gnomad AFR AF: 0.399

Gnomad AMI AF: 0.677

Gnomad AMR AF: 0.614

Gnomad ASJ AF: 0.553

Gnomad EAS AF: 0.620

Gnomad SAS AF: 0.741

Gnomad FIN AF: 0.572

Gnomad MID AF: 0.585

Gnomad NFE AF: 0.546

Gnomad OTH AF: 0.520

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.524 AC: 79661 AN: 152066 Hom.: 21391 Cov.: 33 AF XY: 0.531 AC XY: 39456 AN XY: 74330

African (AFR) AF: 0.398 AC: 16521 AN: 41472

American (AMR) AF: 0.614 AC: 9389 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.553 AC: 1919 AN: 3470

East Asian (EAS) AF: 0.621 AC: 3211 AN: 5172

South Asian (SAS) AF: 0.741 AC: 3573 AN: 4822

European-Finnish (FIN) AF: 0.572 AC: 6049 AN: 10566

Middle Eastern (MID) AF: 0.599 AC: 176 AN: 294

European-Non Finnish (NFE) AF: 0.546 AC: 37105 AN: 67968

Other (OTH) AF: 0.522 AC: 1101 AN: 2110

Alfa AF: 0.543 Hom.: 72053

Bravo AF: 0.518

Asia WGS AF: 0.665 AC: 2314 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	13
DANN	Benign	0.83
PhyloP100		0.16
Mutation Taster		=100/0	polymorphism (auto)

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

dbSNP: rs6726395; hg19: chr2-178103229;