rs281865137

Positions:

• chr10-62813496-C-A
• chr10-62813496-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_000399.5(EGR2):​c.1142G>T​(p.Arg381Leu) 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 NM_000399.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• 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 16 ACMG points.

• PM1: In a zinc_finger_region C2H2-type 2 (size 22) in uniprot entity EGR2_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000399.5
• 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 Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.895
• PP5: Variant 10-62813496-C-A is Pathogenic according to our data. Variant chr10-62813496-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 1075624.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EGR2	NM_000399.5	c.1142G>T	p.Arg381Leu	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>T	p.Arg381Leu	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:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 10, 2020

Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32376792, 30889162) -

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 04, 2020

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 determined to be pathogenic (PMID: 10762521, 11239949, 12471219, 20513111, 25720245). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed in individual(s) with autosomal dominant Charcot-Marie-Tooth disease (PMID: 30889162). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with leucine at codon 381 of the EGR2 protein (p.Arg381Leu). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and leucine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D;.;D
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	.;D;D
M_CAP	Benign	0.047	D
MetaRNN	Pathogenic	0.90	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	-6.6	D;D;D
REVEL	Uncertain	0.42
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.98	D;D;D
Vest4		0.79
MutPred		0.77		Loss of MoRF binding (P = 0.0133);.;Loss of MoRF binding (P = 0.0133);
MVP		0.87
MPC		2.1
ClinPred		1.0	D
GERP RS		3.9
Varity_R		0.89
gMVP		0.95

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-64573256;