1-12004010-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 5P and 2B. PM1PM2PP2BP4_Moderate

The NM_014874.4(MFN2):​c.1179G>C​(p.Met393Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000867 in 1,614,144 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 (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M393V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

MFN2
NM_014874.4 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.949
Variant links:
Genes affected
MFN2 (HGNC:16877): (mitofusin 2) This gene encodes a mitochondrial membrane protein that participates in mitochondrial fusion and contributes to the maintenance and operation of the mitochondrial network. This protein is involved in the regulation of vascular smooth muscle cell proliferation, and it may play a role in the pathophysiology of obesity. Mutations in this gene cause Charcot-Marie-Tooth disease type 2A2, and hereditary motor and sensory neuropathy VI, which are both disorders of the peripheral nervous system. Defects in this gene have also been associated with early-onset stroke. Two transcript variants encoding the same protein have been identified. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM1
In a helix (size 66) in uniprot entity MFN2_HUMAN there are 51 pathogenic changes around while only 1 benign (98%) in NM_014874.4
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in the MFN2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 123 curated pathogenic missense variants (we use a threshold of 10). The gene has 23 curated benign missense variants. Gene score misZ: 1.6575 (below the threshold of 3.09). Trascript score misZ: 3.2174 (above the threshold of 3.09). GenCC associations: The gene is linked to Charcot-Marie-Tooth disease type 2A2, axonal hereditary motor and sensory neuropathy, hereditary motor and sensory neuropathy type 6, Charcot-Marie-Tooth disease, axonal, autosomal recessive, type 2a2b;, multiple symmetric lipomatosis, severe early-onset axonal neuropathy due to MFN2 deficiency.
BP4
Computational evidence support a benign effect (MetaRNN=0.09621632).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MFN2NM_014874.4 linkc.1179G>C p.Met393Ile missense_variant Exon 12 of 19 ENST00000235329.10 NP_055689.1 O95140-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MFN2ENST00000235329.10 linkc.1179G>C p.Met393Ile missense_variant Exon 12 of 19 1 NM_014874.4 ENSP00000235329.5 O95140-1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152262
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000159
AC:
4
AN:
251490
Hom.:
0
AF XY:
0.0000294
AC XY:
4
AN XY:
135922
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000352
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000889
AC:
13
AN:
1461882
Hom.:
0
Cov.:
32
AF XY:
0.0000110
AC XY:
8
AN XY:
727242
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000117
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152262
Hom.:
0
Cov.:
33
AF XY:
0.0000134
AC XY:
1
AN XY:
74388
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.00000460
Hom.:
0
Bravo
AF:
0.0000113
ExAC
AF:
0.0000247
AC:
3
EpiCase
AF:
0.00
EpiControl
AF:
0.000119

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Dec 27, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1179G>C (p.M393I) alteration is located in exon 12 (coding exon 10) of the MFN2 gene. This alteration results from a G to C substitution at nucleotide position 1179, causing the methionine (M) at amino acid position 393 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.20
BayesDel_addAF
Benign
-0.060
T
BayesDel_noAF
Benign
-0.22
CADD
Benign
18
DANN
Benign
0.96
DEOGEN2
Benign
0.20
T;T
Eigen
Benign
-0.60
Eigen_PC
Benign
-0.48
FATHMM_MKL
Benign
0.65
D
LIST_S2
Benign
0.84
T;.
M_CAP
Benign
0.058
D
MetaRNN
Benign
0.096
T;T
MetaSVM
Benign
-0.46
T
MutationAssessor
Benign
0.69
N;N
PrimateAI
Benign
0.35
T
PROVEAN
Benign
-0.76
N;N
REVEL
Benign
0.16
Sift
Benign
0.19
T;T
Sift4G
Benign
0.19
T;T
Polyphen
0.0010
B;B
Vest4
0.20
MutPred
0.35
Gain of sheet (P = 0.0011);Gain of sheet (P = 0.0011);
MVP
0.52
MPC
0.23
ClinPred
0.073
T
GERP RS
1.2
Varity_R
0.16
gMVP
0.58

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs12069578; hg19: chr1-12064067; API