rs538243357
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP2
The NM_014874.4(MFN2):c.1181G>A(p.Arg394His) variant causes a missense change. The variant allele was found at a frequency of 0.0000489 in 1,614,118 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R394C) has been classified as Uncertain significance.
Frequency
Consequence
NM_014874.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MFN2 | NM_014874.4 | c.1181G>A | p.Arg394His | missense_variant | 12/19 | ENST00000235329.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MFN2 | ENST00000235329.10 | c.1181G>A | p.Arg394His | missense_variant | 12/19 | 1 | NM_014874.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000328 AC: 5AN: 152242Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000676 AC: 17AN: 251486Hom.: 0 AF XY: 0.0000956 AC XY: 13AN XY: 135918
GnomAD4 exome AF: 0.0000506 AC: 74AN: 1461876Hom.: 1 Cov.: 32 AF XY: 0.0000564 AC XY: 41AN XY: 727238
GnomAD4 genome ? AF: 0.0000328 AC: 5AN: 152242Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74380
ClinVar
Submissions by phenotype
Charcot-Marie-Tooth disease Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Molecular Genetics Laboratory, London Health Sciences Centre | - | - - |
Charcot-Marie-Tooth disease type 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jun 27, 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 expected to disrupt MFN2 protein function. ClinVar contains an entry for this variant (Variation ID: 568120). This missense change has been observed in individual(s) with Charcot-Marie-Tooth disease (PMID: 32376792). This variant is present in population databases (rs538243357, gnomAD 0.03%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 394 of the MFN2 protein (p.Arg394His). - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Sep 08, 2019 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at