10-62814446-C-G
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2BP4_StrongBP6BS1
The NM_000399.5(EGR2):c.192G>C(p.Met64Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000295 in 1,613,982 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 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. M64V) has been classified as Uncertain significance.
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.192G>C | p.Met64Ile | missense_variant | 2/2 | ENST00000242480.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
EGR2 | ENST00000242480.4 | c.192G>C | p.Met64Ile | missense_variant | 2/2 | 1 | NM_000399.5 | A1 | |
ENST00000493899.2 | n.673G>C | non_coding_transcript_exon_variant | 8/8 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.000230 AC: 35AN: 152036Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000398 AC: 100AN: 251476Hom.: 0 AF XY: 0.000427 AC XY: 58AN XY: 135910
GnomAD4 exome AF: 0.000302 AC: 441AN: 1461828Hom.: 1 Cov.: 31 AF XY: 0.000305 AC XY: 222AN XY: 727214
GnomAD4 genome ? AF: 0.000230 AC: 35AN: 152154Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12AN XY: 74390
ClinVar
Submissions by phenotype
not provided Uncertain:5
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Sep 01, 2023 | The EGR2 c.192G>C; p.Met64Ile variant (rs146631014) is reported in the literature in multiple individuals affected with Charcot-Marie-Tooth (Volodarsky 2021). This variant is also reported in ClinVar (Variation ID: 246186). This variant is found in the non-Finnish European population with an allele frequency of 0.07% (88/129154 alleles) in the Genome Aggregation Database. Computational analyses predict that this variant is neutral (REVEL: 0.103). However, given the lack of clinical and functional data, the significance of this variant is uncertain at this time. References: Volodarsky M et al. Comprehensive genetic sequence and copy number analysis for Charcot-Marie-Tooth disease in a Canadian cohort of 2517 patients. J Med Genet. 2021 Apr;58(4):284-288. PMID: 32376792 - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jun 01, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Aug 11, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jun 23, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 12, 2023 | In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32376792) - |
Tip-toe gait Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino | - | - - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 18, 2022 | The p.M64I variant (also known as c.192G>C), located in coding exon 2 of the EGR2 gene, results from a G to C substitution at nucleotide position 192. The methionine at codon 64 is replaced by isoleucine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the supporting evidence, this variant is unlikely to be causative of autosomal dominant Charcot-Marie-Tooth disease, type 1D (CMT1D) and Dejerine-Sottas disease (DSS); however, its contribution to the autosomal recessive spectrum of diseases is uncertain. - |
not specified Benign:1
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | May 28, 2021 | - - |
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 29, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at