Genetic Variant EGR2:p.Leu31Ile (chr10-62815939-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000399.5(EGR2):c.91C>A(p.Leu31Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L31F) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

EGR2
NM_000399.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.13

Publications

0 publications found

Variant links:

Genes affected

EGR2 (HGNC:3239): (early growth response 2) The protein encoded by this gene is a transcription factor with three tandem C2H2-type zinc fingers. Defects in this gene are associated with Charcot-Marie-Tooth disease type 1D (CMT1D), Charcot-Marie-Tooth disease type 4E (CMT4E), and with Dejerine-Sottas syndrome (DSS). Multiple transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Oct 2008]

EGR2 Gene-Disease associations (from GenCC):

Charcot-Marie-Tooth disease type 4E
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
Charcot-Marie-Tooth disease
Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen
Charcot-Marie-Tooth disease type 1D
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
Charcot-Marie-Tooth disease type 3
Inheritance: SD, AD Classification: MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet

EGR2 links:

ENSG00000289487 (HGNC:):

ENSG00000289487 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.08938587).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000399.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EGR2	NM_000399.5	MANE Select	c.91C>A	p.Leu31Ile	missense	Exon 1 of 2	NP_000390.2
EGR2	NM_001410931.1		c.130C>A	p.Leu44Ile	missense	Exon 2 of 3	NP_001397860.1	A0A8I5KYI5
EGR2	NM_001136177.3		c.91C>A	p.Leu31Ile	missense	Exon 2 of 3	NP_001129649.1	P11161-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EGR2	ENST00000242480.4	TSL:1 MANE Select	c.91C>A	p.Leu31Ile	missense	Exon 1 of 2	ENSP00000242480.3	P11161-1
EGR2	ENST00000439032.6	TSL:1	n.91C>A		non_coding_transcript_exon	Exon 1 of 2	ENSP00000509775.1	A0A8I5KVU0
EGR2	ENST00000691610.1		c.130C>A	p.Leu44Ile	missense	Exon 2 of 3	ENSP00000509830.1	A0A8I5KYI5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.60

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.34

Eigen

Benign

-0.34

Eigen_PC

Benign

-0.084

FATHMM_MKL

Benign

0.00065

LIST_S2

Benign

0.68

M_CAP

Benign

0.0027

MetaRNN

Benign

0.089

MetaSVM

Benign

-0.93

MutationAssessor

Benign

-0.30

PhyloP100

3.1

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-0.64

REVEL

Benign

0.038

Sift

Benign

0.37

Sift4G

Benign

0.56

Polyphen

0.012

Vest4

0.17

MutPred

0.30

Gain of sheet (P = 0.0221)

MVP

0.25

MPC

0.95

ClinPred

0.49

GERP RS

4.2

PromoterAI

0.086

Neutral

(source)

Varity_R

0.080

gMVP

0.10

Mutation Taster

=92/8

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over