1-11992584-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP2PP3PP5

The NM_014874.4(MFN2):​c.205G>T​(p.Val69Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V69I) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 31)

Consequence

MFN2
NM_014874.4 missense

Scores

6
8
5

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 3.89
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 Likely_pathogenic. Variant got 7 ACMG points.

PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain 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.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.792
PP5
Variant 1-11992584-G-T is Pathogenic according to our data. Variant chr1-11992584-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 2273.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-11992584-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MFN2NM_014874.4 linkc.205G>T p.Val69Phe missense_variant Exon 4 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.205G>T p.Val69Phe missense_variant Exon 4 of 19 1 NM_014874.4 ENSP00000235329.5 O95140-1

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
31

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Charcot-Marie-Tooth disease type 2A2 Pathogenic:1
May 11, 2004
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.32
BayesDel_addAF
Pathogenic
0.50
D
BayesDel_noAF
Pathogenic
0.48
CADD
Uncertain
25
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.59
D;D;.
Eigen
Benign
0.18
Eigen_PC
Benign
0.19
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.93
D;.;D
M_CAP
Uncertain
0.28
D
MetaRNN
Pathogenic
0.79
D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Uncertain
2.2
M;M;.
PrimateAI
Uncertain
0.60
T
PROVEAN
Uncertain
-3.1
D;D;D
REVEL
Pathogenic
0.69
Sift
Uncertain
0.0030
D;D;D
Sift4G
Benign
0.25
T;T;D
Polyphen
0.82
P;P;.
Vest4
0.78
MutPred
0.42
Gain of helix (P = 0.0117);Gain of helix (P = 0.0117);Gain of helix (P = 0.0117);
MVP
0.98
MPC
1.4
ClinPred
0.94
D
GERP RS
5.4
Varity_R
0.78
gMVP
0.87

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: rs28940296; hg19: chr1-12052641; API