2-177234076-C-T

Position:

• chr2-177234076-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 7P and 1B. PS1_Moderate PM1 PM2 PP5 BP4

The NM_006164.5(NFE2L2):​c.241G>A​(p.Gly81Ser) 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 benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G81D) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: NFE2L2 NM_006164.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.57

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 Likely_pathogenic. Variant got 6 ACMG points.

• PS1: Transcript NM_006164.5 (NFE2L2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_006164.5
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-177234076-C-T is Pathogenic according to our data. Variant chr2-177234076-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 445149.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.39075303). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NFE2L2	NM_006164.5	c.241G>A	p.Gly81Ser	missense_variant	2/5	ENST00000397062.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NFE2L2	ENST00000397062.8	c.241G>A	p.Gly81Ser	missense_variant	2/5	1	NM_006164.5	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Immunodeficiency, developmental delay, and hypohomocysteinemia Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 30, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	33
DANN	Uncertain	0.99
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.066	D
MetaRNN	Benign	0.39	T
MetaSVM	Uncertain	-0.23	T
MutationTaster	Benign	1.0	D;D;D;D;D
PROVEAN	Benign	-0.62	N
REVEL	Benign	0.17
Sift	Benign	0.19	T
MutPred		0.12		Gain of glycosylation at A65 (P = 0.0235);
MVP		0.59
ClinPred		1.0	D
GERP RS		5.8

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: rs1553487942; hg19: chr2-178098804; COSMIC: COSV67960680; COSMIC: COSV67960680;