rs139147487
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2BP4_StrongBP6BS1
The NM_000399.5(EGR2):c.644C>T(p.Thr215Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000702 in 1,614,182 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T215T) has been classified as Likely benign.
Frequency
Consequence
NM_000399.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
EGR2 | NM_000399.5 | c.644C>T | p.Thr215Met | missense_variant | 2/2 | ENST00000242480.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
EGR2 | ENST00000242480.4 | c.644C>T | p.Thr215Met | missense_variant | 2/2 | 1 | NM_000399.5 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.000368 AC: 56AN: 152174Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000644 AC: 162AN: 251472Hom.: 0 AF XY: 0.000721 AC XY: 98AN XY: 135918
GnomAD4 exome AF: 0.000737 AC: 1077AN: 1461890Hom.: 1 Cov.: 31 AF XY: 0.000708 AC XY: 515AN XY: 727248
GnomAD4 genome ? AF: 0.000368 AC: 56AN: 152292Hom.: 0 Cov.: 32 AF XY: 0.000349 AC XY: 26AN XY: 74492
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 08, 2023 | Reported previously as a variant of uncertain significance in two patients with suspected CMT; however, no further clinical or segregation information was provided (Volodarsky et al., 2021); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32376792) - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2016 | - - |
EGR2-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 20, 2023 | The EGR2 c.644C>T variant is predicted to result in the amino acid substitution p.Thr215Met. This variant was reported in two individuals from a Charcot-Marie-Tooth disease cohort (Supplementary Table 2 in Volodarsky et al. 2021. PubMed ID: 32376792). This variant is reported in 0.11% of alleles in individuals of European (Non-Finnish) descent in gnomAD, which may be too frequent for a disease-causing variant in EGR2. This variant has conflicting interpretations in ClinVar ranging from uncertain to likely benign (https://preview.ncbi.nlm.nih.gov/clinvar/variation/246013/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 01, 2019 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Charcot-Marie-Tooth disease type 1D Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. - |
Charcot-Marie-Tooth disease, type I Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 18, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at