rs119103266

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Moderate

The NM_014874.4(MFN2):​c.617C>T​(p.Thr206Ile) variant causes a missense change involving the alteration of a conserved nucleotide. 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T206A) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

MFN2
NM_014874.4 missense

Scores

11
6
2

Clinical Significance

Pathogenic criteria provided, single submitter P:2U:1

Conservation

PhyloP100: 7.54
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 13 ACMG points.

PM1
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_014874.4
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr1-11998786-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 801442.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), MFN2. . Gene score misZ 1.6575 (greater than the threshold 3.09). Trascript score misZ 3.2174 (greater than threshold 3.09). GenCC has associacion of gene with 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, 0.949
PP5
Variant 1-11998787-C-T is Pathogenic according to our data. Variant chr1-11998787-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 2279.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-11998787-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
MFN2NM_014874.4 linkuse as main transcriptc.617C>T p.Thr206Ile missense_variant 7/19 ENST00000235329.10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MFN2ENST00000235329.10 linkuse as main transcriptc.617C>T p.Thr206Ile missense_variant 7/191 NM_014874.4 P1O95140-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:2Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Hereditary motor and sensory neuropathy with optic atrophy Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMFeb 01, 2006- -
not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingInstitute of Medical Genetics and Applied Genomics, University Hospital TübingenOct 23, 2020- -
Charcot-Marie-Tooth disease Uncertain:1
Uncertain significance, no assertion criteria providedresearchGenesis Genome DatabaseAug 14, 2019- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.97
BayesDel_addAF
Pathogenic
0.48
D
BayesDel_noAF
Pathogenic
0.45
CADD
Pathogenic
30
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.87
D;D
Eigen
Uncertain
0.47
Eigen_PC
Uncertain
0.54
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.99
D;.
M_CAP
Pathogenic
0.32
D
MetaRNN
Pathogenic
0.95
D;D
MetaSVM
Uncertain
0.74
D
MutationAssessor
Benign
1.7
L;L
MutationTaster
Benign
1.0
A;A;A
PrimateAI
Pathogenic
0.91
D
PROVEAN
Pathogenic
-4.4
D;D
REVEL
Pathogenic
0.89
Sift
Uncertain
0.0030
D;D
Sift4G
Uncertain
0.0050
D;D
Polyphen
0.61
P;P
Vest4
0.83
MutPred
0.84
Loss of catalytic residue at T206 (P = 0.0099);Loss of catalytic residue at T206 (P = 0.0099);
MVP
0.98
MPC
1.1
ClinPred
0.98
D
GERP RS
5.2
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.73
gMVP
0.94

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.040
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: rs119103266; hg19: chr1-12058844; API