ENST00000699346.1:c.184-31038A>C

Variant names:

• chr2-177265309-T-G
• rs6721961
• ENST00000699346.1:c.184-31038A>C

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

<-10 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -12 classification points (ACMG Germline Pathogenicity v2019). BA1BP4_Strong

The ENST00000699346.1(NFE2L2):c.184-31038A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. Note: ENST00000699346.1 is not a MANE Select or MANE Plus Clinical transcript for NFE2L2; the reported annotation may differ from that of the MANE-designated reference transcript for this gene. The variant allele was found at a cumulative frequency of 0.878 (AC=187,787) in the gnomAD database across 213,946 control chromosomes, including 82,704 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.921. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.88 (59765 hom., cov: 34)
  • Exomes 𝑓: 0.86 (22939 hom.)
• Consequence: NFE2L2 ENST00000699346.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.221
• Publications: 184 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, PanelApp Australia, Illumina, Labcorp Genetics (formerly Invitae)

ENSG00000222043 (HGNC:):

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Benign. The variant received -12 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); No splicing predictor data available.; Germline computational verdict: benign (Strong).
	BA1Stand-alone benign allele frequency (>5%)		GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.9214 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

Automated classification analysis was done for transcript: ENST00000699346.1. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

There are no transcript annotations for this variant.

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	NFE2L2 ENST00000699346.1		c.184-31038A>C	intron	Intron 7 of 10	Prot: ENSP00000514321.1 UniProt:
	NFE2L2 ENST00000586532.6	TSL:5	c.43-31038A>C	intron	Intron 3 of 6	Prot: ENSP00000464920.2 UniProt:
	NFE2L2 ENST00000699265.1		c.43-31038A>C	intron	Intron 5 of 8	Prot: ENSP00000514246.1 UniProt:

NFE2L2 ENST00000699346.1

HGVSc / HGVSpc.184-31038A>C

Exon rankIntron 7 of 10

intron

Prot: ENSP00000514321.1UniProt: A0A8V8TNM0

NFE2L2 ENST00000586532.6

TSL:5

HGVSc / HGVSpc.43-31038A>C

Exon rankIntron 3 of 6

intron

Prot: ENSP00000464920.2UniProt: K7EIW5

NFE2L2 ENST00000699265.1

HGVSc / HGVSpc.43-31038A>C

Exon rankIntron 5 of 8

intron

Prot: ENSP00000514246.1UniProt: K7EIW5

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 5 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.884	AC:134590	Hom:59705	AN:152168	Cov:34
GnomAD4 exome	AF: 0.861	AC:53083	Hom:22939	AN:61660	Cov:0
GnomAD4 genome	AF: 0.885	AC:134704	Hom:59765	AN:152286	Cov:34
TOPMed (Bravo)	AF: 0.886	AC:234398	Hom:104178	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.889	AC:90218	Hom:40081	AN:101436	Cov:
Local & regional cohorts 10 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.887	AC:2077	Hom:925	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.721	AC:	Hom:	AN:	Cov:
Denmark Genome	AF: 0.913	AC:274	Hom:	AN:300	Cov:
GenomeAsia100K	AF: 0.820	AC:2853	Hom:	AN:3478	Cov:
Korea4K (4,157 Koreans)	AF: 0.701	AC:5073	Hom:	AN:7234	Cov:
Qatari Genome	AF: 0.938	AC:165	Hom:	AN:176	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.737	AC:90457	Hom:33327	AN:122714	Cov:
Turkish Variome	AF: 0.830	AC:1283	Hom:533	AN:1546	Cov:
UK10K	AF: 0.900	AC:6807	Hom:	AN:7562	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.727	AC:6516	Hom:2385	AN:8960	Cov:

Showing 15 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
SCHEMA(Schizophrenia)	0.442	11767	26610	0.267	9187	34418

Showing 1 cohortAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	10
BayesDel_noAF	Benign	-0.79
CADD	Benign	8.4
DANN	Benign	0.64
GPN-Star LLR	N/A	6.7
GPN-Star score	N/A	1.9
Mutation Taster	N/A	99/1	polymorphism (auto)
PhyloP100	Benign	0.22
PromoterAI	N/A	0.022	Neutral

Showing 9 of 9 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0

Showing 1 of 1 scores

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.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs6721961;

hg19: chr2-178130037;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar