2-177234226-C-T

Variant names:

• chr2-177234226-C-T
• rs1553488015
• NM_006164.5:c.91G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_006164.5(NFE2L2):​c.91G>A​(p.Gly31Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: NFE2L2 NM_006164.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 7.57
• Publications: 1 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.827
• PP5: Variant 2-177234226-C-T is Pathogenic according to our data. Variant chr2-177234226-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 445150.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NFE2L2	NM_006164.5	c.91G>A	p.Gly31Arg	missense_variant	Exon 2 of 5	ENST00000397062.8	NP_006155.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NFE2L2	ENST00000397062.8	c.91G>A	p.Gly31Arg	missense_variant	Exon 2 of 5	1	NM_006164.5	ENSP00000380252.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Immunodeficiency, developmental delay, and hypohomocysteinemia Pathogenic:1

Aug 28, 2018

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Colorectal cancer Pathogenic:1

Nov 27, 2017

Oxford Haemato-Oncology Service, Oxford University Hospitals NHS Foundation Trust

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Deregulation in NFE2L2 have been associated with anti-oxydant metabolism deregulation during chemotherapy. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.20
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	.;T;.;.;.;T;T;.;.;.
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	.;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.83	D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.42	T
MutationAssessor	Pathogenic	3.1	.;M;.;.;.;.;.;.;.;.
PhyloP100		7.6
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-5.5	D;D;D;.;N;D;.;D;D;.
REVEL	Pathogenic	0.70
Sift	Pathogenic	0.0	D;D;D;.;D;D;.;D;D;.
Sift4G	Pathogenic	0.0	D;D;D;D;.;.;D;.;D;.
Polyphen		1.0	.;D;.;.;.;.;.;.;D;.
Vest4		0.79
MutPred		0.58		.;Gain of solvent accessibility (P = 0.0055);.;.;.;.;.;.;.;.;
MVP		0.63
MPC		0.69
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.85
gMVP		0.71
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1553488015; hg19: chr2-178098954; COSMIC: COSV67961406; COSMIC: COSV67961406;