2-177231801-C-T

Variant names:

• chr2-177231801-C-T
• rs34154613
• NM_006164.5:c.802G>A
• NFE2L2 p.Val268Met

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_006164.5(NFE2L2):​c.802G>A​(p.Val268Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00413 in 1,614,212 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0025 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0043 (32 hom.)
• Consequence: NFE2L2 NM_006164.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3 O:1
• Conservation: PhyloP100: 0.963
• Publications: 13 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: Illumina, ClinGen, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005718589).
• BP6: Variant 2-177231801-C-T is Benign according to our data. Variant chr2-177231801-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 134906.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 382 AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NFE2L2	NM_006164.5	MANE Select	c.802G>A	p.Val268Met	missense	Exon 5 of 5	NP_006155.2
	NFE2L2	NM_001145412.3		c.754G>A	p.Val252Met	missense	Exon 5 of 5	NP_001138884.1	Q16236-2
	NFE2L2	NM_001313900.1		c.754G>A	p.Val252Met	missense	Exon 5 of 5	NP_001300829.1	Q16236-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NFE2L2	ENST00000397062.8	TSL:1 MANE Select	c.802G>A	p.Val268Met	missense	Exon 5 of 5	ENSP00000380252.3	Q16236-1
	NFE2L2	ENST00000397063.9	TSL:1	c.754G>A	p.Val252Met	missense	Exon 5 of 5	ENSP00000380253.4	Q16236-2
	NFE2L2	ENST00000421929.6	TSL:1	c.754G>A	p.Val252Met	missense	Exon 5 of 5	ENSP00000412191.2	Q16236-2

Frequencies

GnomAD3 genomes AF: 0.00251 AC: 382 AN: 152212 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000603

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00424

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00422

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00241 AC: 601 AN: 249402 AF XY: 0.00230

Gnomad AFR exome AF: 0.000581

Gnomad AMR exome AF: 0.00122

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00473

Gnomad NFE exome AF: 0.00385

Gnomad OTH exome AF: 0.00198

GnomAD4 exome AF: 0.00430 AC: 6284 AN: 1461882 Hom.: 32 Cov.: 31 AF XY: 0.00415 AC XY: 3020 AN XY: 727244

African (AFR) AF: 0.000508 AC: 17 AN: 33480

American (AMR) AF: 0.00123 AC: 55 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00461 AC: 246 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00517 AC: 5751 AN: 1112000

Other (OTH) AF: 0.00354 AC: 214 AN: 60396

GnomAD4 genome AF: 0.00251 AC: 382 AN: 152330 Hom.: 1 Cov.: 32 AF XY: 0.00227 AC XY: 169 AN XY: 74492

African (AFR) AF: 0.000601 AC: 25 AN: 41582

American (AMR) AF: 0.00157 AC: 24 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00424 AC: 45 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00422 AC: 287 AN: 68030

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.00355 Hom.: 2

Bravo AF: 0.00260

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00398

EpiControl AF: 0.00373

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	NFE2L2-related disorder (1)
-	-	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	16
DANN	Benign	0.91
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.52	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.0077	T
MetaRNN	Benign	0.0057	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L
PhyloP100		0.96
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.050	N
REVEL	Benign	0.088
Sift	Benign	0.18	T
Sift4G	Benign	0.31	T
Varity_R		0.071
gMVP		0.21
Mutation Taster		=99/1	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs34154613; hg19: chr2-178096529; COSMIC: COSV67962738; COSMIC: COSV67962738;