rs751448371
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PM5PP5
The NM_000399.5(EGR2):c.1066G>C(p.Glu356Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E356K) has been classified as Likely pathogenic.
Frequency
Genomes: not found (cov: 32)
Consequence
EGR2
NM_000399.5 missense
NM_000399.5 missense
Scores
3
8
7
Clinical Significance
Conservation
PhyloP100: 6.16
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
PM1
?
In a zinc_finger_region C2H2-type 1 (size 24) in uniprot entity EGR2_HUMAN there are 7 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 chr10-62813572-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 577101.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP5
?
Variant 10-62813572-C-G is Pathogenic according to our data. Variant chr10-62813572-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 391755.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
EGR2 | NM_000399.5 | c.1066G>C | p.Glu356Gln | missense_variant | 2/2 | ENST00000242480.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
EGR2 | ENST00000242480.4 | c.1066G>C | p.Glu356Gln | missense_variant | 2/2 | 1 | NM_000399.5 | A1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 07, 2017 | The E356Q variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The E356Q variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server. The E356Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Additionally, multiple missense variants in nearby residues have been reported in Human Gene Mutation Database in association with EGR2-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. - |
Charcot-Marie-Tooth disease, type I Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 22, 2017 | This sequence change replaces glutamic acid with glutamine at codon 356 of the EGR2 protein (p.Glu356Gln). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and glutamine. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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 not been reported in the literature in individuals with EGR2-related disease. ClinVar contains an entry for this variant (Variation ID: 391755). This variant is not present in population databases (ExAC no frequency). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
D;.;D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
M_CAP
Benign
T
MetaRNN
Uncertain
T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
N;.;N
MutationTaster
Benign
D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;D;D
REVEL
Benign
Sift
Uncertain
D;D;D
Sift4G
Pathogenic
D;D;D
Polyphen
D;D;D
Vest4
MutPred
Gain of MoRF binding (P = 0.0215);.;Gain of MoRF binding (P = 0.0215);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at