2-177231801-C-T

Variant summary

Our verdict is Benign. Variant got -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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• 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

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]

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 134906.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 382 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NFE2L2	NM_006164.5	c.802G>A	p.Val268Met	missense_variant	5/5	ENST00000397062.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NFE2L2	ENST00000397062.8	c.802G>A	p.Val268Met	missense_variant	5/5	1	NM_006164.5	A1

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

GnomAD3 exomes AF: 0.00241 AC: 601 AN: 249402 Hom.: 2 AF XY: 0.00230 AC XY: 311 AN XY: 135312

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 SAS 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

Gnomad4 AFR exome AF: 0.000508

Gnomad4 AMR exome AF: 0.00123

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00461

Gnomad4 NFE exome AF: 0.00517

Gnomad4 OTH exome AF: 0.00354

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

Gnomad4 AFR AF: 0.000601

Gnomad4 AMR AF: 0.00157

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00424

Gnomad4 NFE AF: 0.00422

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00384 Hom.: 2

Bravo AF: 0.00260

TwinsUK AF: 0.00674 AC: 25

ALSPAC AF: 0.00415 AC: 16

ESP6500AA AF: 0.00130 AC: 5

ESP6500EA AF: 0.00422 AC: 35

ExAC AF: 0.00240 AC: 290

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00398

EpiControl AF: 0.00373

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	NFE2L2: BP4, BS2 -

NFE2L2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 05, 2019

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

not specified Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

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
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.52	D
M_CAP	Benign	0.0077	T
MetaRNN	Benign	0.0057	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.050	N;N;N;.;N;N
REVEL	Benign	0.088
Sift	Benign	0.18	T;T;T;.;T;T
Sift4G	Benign	0.31	T;T;T;T;.;T
Polyphen		0.0080	.;B;.;.;.;.
Vest4		0.085
MVP		0.35
MPC		0.17
ClinPred		0.0046	T
GERP RS		2.4
Varity_R		0.071
gMVP		0.21

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

Other links and lift over

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