rs138967272

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000399.5(EGR2):c.1352G>T(p.Gly451Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000591 in 1,572,584 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G451D) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00062 ( 16 hom. )

Consequence

EGR2
NM_000399.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:2B:6

Conservation

PhyloP100: 0.765

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003899008).

BP6

Variant 10-62813286-C-A is Benign according to our data. Variant chr10-62813286-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 219918.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-62813286-C-A is described in Lovd as [Pathogenic].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000328 (50/152356) while in subpopulation SAS AF= 0.00932 (45/4830). AF 95% confidence interval is 0.00716. There are 0 homozygotes in gnomad4. There are 36 alleles in male gnomad4 subpopulation. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome at 3 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EGR2	NM_000399.5 linkuse as main transcript	c.1352G>T	p.Gly451Val	missense_variant	2/2	ENST00000242480.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EGR2	ENST00000242480.4 linkuse as main transcript	c.1352G>T	p.Gly451Val	missense_variant	2/2	1	NM_000399.5	A1	P11161-1

Frequencies

GnomAD3 genomes

AF:

0.000335

AC:

AN:

152238

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00952

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00107

AC:

234

AN:

218404

Hom.:

AF XY:

0.00145

AC XY:

167

AN XY:

115490

show subpopulations

Gnomad AFR exome

AF:

0.0000625

Gnomad AMR exome

AF:

0.0000312

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00950

Gnomad FIN exome

AF:

0.0000529

Gnomad NFE exome

AF:

0.000111

Gnomad OTH exome

AF:

0.00114

GnomAD4 exome

AF:

0.000619

AC:

879

AN:

1420228

Hom.:

Cov.:

AF XY:

0.000873

AC XY:

612

AN XY:

700836

show subpopulations

Gnomad4 AFR exome

AF:

0.000244

Gnomad4 AMR exome

AF:

0.0000238

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00925

Gnomad4 FIN exome

AF:

0.0000196

Gnomad4 NFE exome

AF:

0.0000817

Gnomad4 OTH exome

AF:

0.000854

GnomAD4 genome

AF:

0.000328

AC:

AN:

152356

Hom.:

Cov.:

AF XY:

0.000483

AC XY:

AN XY:

74510

show subpopulations

Gnomad4 AFR

AF:

0.0000962

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00932

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000119

Hom.:

Bravo

AF:

0.000155

ExAC

AF:

0.00104

AC:

126

Asia WGS

AF:

0.00520

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:2Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Charcot-Marie-Tooth disease type 1D

Uncertain:1Benign:2

Uncertain significance, no assertion criteria provided	literature only	Inherited Neuropathy Consortium Ii, University Of Miami	Jan 06, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Charcot-Marie-Tooth disease

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Molecular Genetics Laboratory, London Health Sciences Centre	-	- -
Uncertain significance, no assertion criteria provided	literature only	Inherited Neuropathy Consortium	-	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2022	EGR2: BP4, BS1 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 11, 2021	This variant is associated with the following publications: (PMID: 28902413, 11545686, 22765307) -

Charcot-Marie-Tooth disease, type I

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Nov 15, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.34

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.28

Cadd

Benign

9.8

Dann

Benign

0.75

DEOGEN2

Benign

0.38

T;.;T

Eigen

Benign

-0.94

Eigen_PC

Benign

-0.90

FATHMM_MKL

Benign

0.18

MetaRNN

Benign

0.0039

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.81

L;.;L

MutationTaster

Benign

0.86

D;D;D

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.50

N;N;N

REVEL

Benign

0.23

Sift

Uncertain

0.0030

D;D;D

Sift4G

Benign

0.53

T;T;T

Polyphen

0.0010

B;B;B

Vest4

0.38

MVP

0.89

MPC

1.1

ClinPred

0.018

GERP RS

2.1

Varity_R

0.10

gMVP

0.68

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over