rs749606728
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM2PP2BP4_Strong
The NM_014874.4(MFN2):āc.1729A>Gā(p.Ile577Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,614,030 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Consequence
NM_014874.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MFN2 | NM_014874.4 | c.1729A>G | p.Ile577Val | missense_variant | 16/19 | ENST00000235329.10 | NP_055689.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MFN2 | ENST00000235329.10 | c.1729A>G | p.Ile577Val | missense_variant | 16/19 | 1 | NM_014874.4 | ENSP00000235329.5 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152162Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251396Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135882
GnomAD4 exome AF: 0.00000410 AC: 6AN: 1461868Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2AN XY: 727234
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152162Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74350
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Oct 09, 2019 | The MFN2 c.1729A>G; p.Ile577Val variant (rs749606728), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 246602). This variant is found on only two chromosomes (2/113698 alleles) in the Genome Aggregation Database. The isoleucine at codon 577 is weakly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. However, due to limited information, the clinical significance of the p.Ile577Val variant is uncertain at this time. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 09, 2018 | The I577V variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The I577V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Isoleucine are tolerated across species. In silico analysis predicts this variant likely does not alter the protein structure/function. 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 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jul 07, 2023 | 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MFN2 protein function. ClinVar contains an entry for this variant (Variation ID: 246602). This variant has not been reported in the literature in individuals affected with MFN2-related conditions. This variant is present in population databases (rs749606728, gnomAD 0.002%). This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 577 of the MFN2 protein (p.Ile577Val). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at