chr2-177234076-C-T

Variant names:

• chr2-177234076-C-T
• rs1553487942
• NM_006164.5:c.241G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 5P and 1B. 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 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
• Publications: 0 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: G2P, ClinGen, Illumina, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• 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 VariationId 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.

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.241G>A	p.Gly81Ser	missense	Exon 2 of 5	NP_006155.2
	NFE2L2	NM_001145412.3		c.193G>A	p.Gly65Ser	missense	Exon 2 of 5	NP_001138884.1	Q16236-2
	NFE2L2	NM_001313900.1		c.193G>A	p.Gly65Ser	missense	Exon 2 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.241G>A	p.Gly81Ser	missense	Exon 2 of 5	ENSP00000380252.3	Q16236-1
	NFE2L2	ENST00000397063.9	TSL:1	c.193G>A	p.Gly65Ser	missense	Exon 2 of 5	ENSP00000380253.4	Q16236-2
	NFE2L2	ENST00000421929.6	TSL:1	c.193G>A	p.Gly65Ser	missense	Exon 2 of 5	ENSP00000412191.2	Q16236-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Immunodeficiency, developmental delay, and hypohomocysteinemia (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		7.6
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
Varity_R		0.89
Mutation Taster		=1/99	disease causing (ClinVar)

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