chr10-62813496-C-T

Position:

• chr10-62813496-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The ENST00000242480.4(EGR2):​c.1142G>A​(p.Arg381His) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R381C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: EGR2 ENST00000242480.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4 U:3 O:1
• Conservation: PhyloP100: 7.89

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in ENST00000242480.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr10-62813497-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 637524.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.945
• PP5: Variant 10-62813496-C-T is Pathogenic according to our data. Variant chr10-62813496-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 41008.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-62813496-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EGR2	NM_000399.5	c.1142G>A	p.Arg381His	missense_variant	2/2	ENST00000242480.4	NP_000390.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EGR2	ENST00000242480.4	c.1142G>A	p.Arg381His	missense_variant	2/2	1	NM_000399.5	ENSP00000242480	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4 Uncertain:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Charcot-Marie-Tooth disease type 1D Pathogenic:1 Uncertain:1 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Uncertain significance, no assertion criteria provided	literature only	Inherited Neuropathy Consortium Ii, University Of Miami	Jan 06, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	CMT Laboratory, Bogazici University	Dec 01, 2020	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	EGR2: PM1, PM2, PM5, PM6, PS4:Moderate, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 12, 2021	This variant was not reported in large, multi-ethnic, general populations (http://gnomad.broadinstitute.org). This variant appears to occur de novo in multiple individuals with clinical features associated with this gene. Assessment of experimental evidence suggests this variant results in abnormal protein function. Multiple studies have shown that this variant results in the loss of transcriptional regulatory activity required for normal myelination (PMID: 11734543, 12609493). -

Charcot-Marie-Tooth disease Uncertain:2

Uncertain significance, no assertion criteria provided	literature only	Inherited Neuropathy Consortium	-	- -
Uncertain significance, no assertion criteria provided	research	Genesis Genome Database	Aug 14, 2019	- -

Charcot-Marie-Tooth disease, type I Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 18, 2023

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 381 of the EGR2 protein (p.Arg381His). This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg381 amino acid residue in EGR2. Other variant(s) that disrupt this residue have been observed in individuals with EGR2-related conditions (PMID: 11239949, 20513111), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this missense change affects EGR2 function (PMID: 12609493). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt EGR2 protein function. ClinVar contains an entry for this variant (Variation ID: 41008). This missense change has been observed in individual(s) with Charcot-Marie-Tooth (CMT) (PMID: 10762521, 12471219, 22765307, 25720245). In at least one individual the variant was observed to be de novo. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.86	D;.;D
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.90	.;D;D
M_CAP	Benign	0.031	D
MetaRNN	Pathogenic	0.95	D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L;.;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-4.7	D;D;D
REVEL	Uncertain	0.42
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.64
MutPred		0.93		Loss of MoRF binding (P = 0.0105);.;Loss of MoRF binding (P = 0.0105);
MVP		0.88
MPC		2.2
ClinPred		1.0	D
GERP RS		3.9
Varity_R		0.80
gMVP		0.86

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

Other links and lift over

dbSNP: rs281865137; hg19: chr10-64573256; COSMIC: COSV54346412; COSMIC: COSV54346412;