rs1178718119

Positions:

• chr10-62815957-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000399.5(EGR2):​c.73A>G​(p.Ile25Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: EGR2 NM_000399.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.343

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]

ENSG00000289487 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13190082).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EGR2	NM_000399.5	c.73A>G	p.Ile25Val	missense_variant	1/2	ENST00000242480.4	NP_000390.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EGR2	ENST00000242480.4	c.73A>G	p.Ile25Val	missense_variant	1/2	1	NM_000399.5	ENSP00000242480.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251484 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135918

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461874 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 24, 2017

In summary, this variant has uncertain impact on EGR2 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with a EGR2-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces isoleucine with valine at codon 25 of the EGR2 protein (p.Ile25Val). The isoleucine residue is weakly conserved and there is a small physicochemical difference between isoleucine and valine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	19
DANN	Benign	0.91
DEOGEN2	Benign	0.30	T;T;T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.00087	N
LIST_S2	Benign	0.65	.;T;T
M_CAP	Benign	0.0028	T
MetaRNN	Benign	0.13	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.42	N;N;.
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.060	N;N;.
REVEL	Benign	0.075
Sift	Benign	0.15	T;T;.
Sift4G	Benign	0.74	T;T;.
Polyphen		0.0	B;B;.
Vest4		0.10
MutPred		0.36		Loss of catalytic residue at I25 (P = 0.0107);Loss of catalytic residue at I25 (P = 0.0107);Loss of catalytic residue at I25 (P = 0.0107);
MVP		0.18
MPC		0.76
ClinPred		0.055	T
GERP RS		3.7
Varity_R		0.044
gMVP		0.14

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1178718119; hg19: chr10-64575717;