rs147136530
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 4P and 6B. PM1PP2PP3BP4BP6BS2
The NM_014874.4(MFN2):āc.842G>Cā(p.Cys281Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000222 in 1,613,878 control chromosomes in the GnomAD database, including 2 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. C281W) has been classified as Uncertain significance.
Frequency
Consequence
NM_014874.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MFN2 | NM_014874.4 | c.842G>C | p.Cys281Ser | missense_variant | 9/19 | ENST00000235329.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MFN2 | ENST00000235329.10 | c.842G>C | p.Cys281Ser | missense_variant | 9/19 | 1 | NM_014874.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000138 AC: 21AN: 152230Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000367 AC: 92AN: 250444Hom.: 0 AF XY: 0.000399 AC XY: 54AN XY: 135494
GnomAD4 exome AF: 0.000231 AC: 337AN: 1461530Hom.: 2 Cov.: 32 AF XY: 0.000275 AC XY: 200AN XY: 727056
GnomAD4 genome ? AF: 0.000138 AC: 21AN: 152348Hom.: 0 Cov.: 33 AF XY: 0.000215 AC XY: 16AN XY: 74504
ClinVar
Submissions by phenotype
not provided Uncertain:4
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jul 15, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Dec 07, 2022 | Reported in families with axonal hereditary motor and sensory neuropathy; however, the authors concluded that C281S is either a benign variant or a pathogenic variant associated with autosomal recessive inheritance as it was identified in healthy relatives with normal electrophysiological examination (Brozkova et al., 2013); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26257172, 24863639, 32376792, 24126688) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 20, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2024 | MFN2: PP3, BP5 - |
Charcot-Marie-Tooth disease type 2 Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 10, 2024 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Charcot-Marie-Tooth disease Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Molecular Genetics Laboratory, London Health Sciences Centre | - | - - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 31, 2022 | The p.C281S variant (also known as c.842G>C), located in coding exon 7 of the MFN2 gene, results from a G to C substitution at nucleotide position 842. The cysteine at codon 281 is replaced by serine, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this variant is unlikely to be causative of autosomal dominant Charcot-Marie-Tooth disease (CMT) type 2A2A and hereditary motor and sensory neuropathy VIA; however, its contribution to the development of autosomal recessive Charcot-Marie-Tooth disease (CMT) type 2A2B is uncertain. - |
Charcot-Marie-Tooth disease, axonal, autosomal recessive, type 2a2b; Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 23, 2020 | This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. - |
Hereditary motor and sensory neuropathy with optic atrophy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Dec 19, 2016 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at