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

Variant names:

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

GermlineCancer (beta)

Variant summary

Our verdict is Likely benign.

-2 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -2 classification points (ACMG Germline Pathogenicity v2019). PM2BP4_Strong

The ENST00000699346.1(NFE2L2):c.184-31038A>T 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 is absent from the gnomAD population database at sites with sufficient sequencing coverage. 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: not found (cov: 34)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• 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: Likely_benign. The variant received -2 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD/XL) (threshold 0.0001) — PM2 moderate.
	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).

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>T	intron	Intron 7 of 10	Prot: ENSP00000514321.1 UniProt:
	NFE2L2 ENST00000586532.6	TSL:5	c.43-31038A>T	intron	Intron 3 of 6	Prot: ENSP00000464920.2 UniProt:
	NFE2L2 ENST00000699265.1		c.43-31038A>T	intron	Intron 5 of 8	Prot: ENSP00000514246.1 UniProt:

NFE2L2 ENST00000699346.1

HGVSc / HGVSpc.184-31038A>T

Exon rankIntron 7 of 10

intron

Prot: ENSP00000514321.1UniProt: A0A8V8TNM0

NFE2L2 ENST00000586532.6

TSL:5

HGVSc / HGVSpc.43-31038A>T

Exon rankIntron 3 of 6

intron

Prot: ENSP00000464920.2UniProt: K7EIW5

NFE2L2 ENST00000699265.1

HGVSc / HGVSpc.43-31038A>T

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 3 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:34
GnomAD4 exome Warning	AF: 0.00	AC:0	Hom:0	AN:61768	Cov:0
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:34

Showing 3 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	11
BayesDel_noAF	Benign	-0.76
CADD	Benign	9.0
DANN	Benign	0.64
GPN-Star LLR	N/A	2.6
GPN-Star score	N/A	-2.3
PhyloP100	Benign	0.22
PromoterAI	N/A	0.017	Neutral

Showing 8 of 8 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