rs144860227
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 5P and 4B. PM1PM2PP2BP4_Strong
The NM_014874.4(MFN2):c.2146G>A(p.Ala716Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000263 in 1,614,182 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict 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. A716P) 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 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MFN2 | NM_014874.4 | c.2146G>A | p.Ala716Thr | missense_variant | 18/19 | ENST00000235329.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MFN2 | ENST00000235329.10 | c.2146G>A | p.Ala716Thr | missense_variant | 18/19 | 1 | NM_014874.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000296 AC: 45AN: 152180Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000107 AC: 27AN: 251490Hom.: 0 AF XY: 0.0000736 AC XY: 10AN XY: 135922
GnomAD4 exome AF: 0.000259 AC: 378AN: 1461884Hom.: 1 Cov.: 32 AF XY: 0.000249 AC XY: 181AN XY: 727248
GnomAD4 genome ? AF: 0.000309 AC: 47AN: 152298Hom.: 0 Cov.: 32 AF XY: 0.000282 AC XY: 21AN XY: 74480
ClinVar
Submissions by phenotype
not provided Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Feb 20, 2018 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 24, 2020 | This variant is associated with the following publications: (PMID: 29361379, 29341354, 20350294, 23106488, 21508331, 22492563, 20482598) - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Dec 01, 2023 | MFN2: PM1, PM2:Supporting, BP4 - |
Charcot-Marie-Tooth disease Pathogenic:1Uncertain:1
Likely pathogenic, flagged submission | clinical testing | Molecular Genetics Laboratory, London Health Sciences Centre | - | - - |
Uncertain significance, no assertion criteria provided | literature only | Inherited Neuropathy Consortium | - | - - |
Charcot-Marie-Tooth disease type 2 Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 04, 2024 | This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 716 of the MFN2 protein (p.Ala716Thr). This variant is present in population databases (rs144860227, gnomAD 0.06%). This missense change has been observed in individual(s) with clinical features of MFN2-related conditions (PMID: 20350294, 21508331, 22492563, 33415332). ClinVar contains an entry for this variant (Variation ID: 214649). 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 with a negative predictive value of 80%. 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. - |
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. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 23, 2022 | The p.A716T variant (also known as c.2146G>A), located in coding exon 16 of the MFN2 gene, results from a G to A substitution at nucleotide position 2146. The alanine at codon 716 is replaced by threonine, an amino acid with similar properties. This variant was reported to segregate with dominant intermediate Charcot Marie Tooth disease in a single family (Braathen GJ et al. BMC Med. Genet., 2010 Mar;11:48) and has also been reported in two individuals affected with Charcot Marie Tooth disease type 2 (Feely SM et al. Neurology, 2011 May;76:1690-6; Sitarz KS et al. Brain, 2012 Aug;135:e219, 1-3; author reply e220, 1-3). This amino acid position is not 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 Charcot-Marie-Tooth disease (CMT) type 2A2A and hereditary motor and sensory neuropathy VIA; however, its contribution to the development of Charcot-Marie-Tooth disease (CMT) type 2A2B is uncertain. - |
Hereditary motor and sensory neuropathy with optic atrophy Benign:1
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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at