rs142271930

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_014874.4(MFN2):c.2113G>A(p.Val705Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00508 in 1,614,164 control chromosomes in the GnomAD database, including 81 homozygotes. 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V705F) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0059 ( 14 hom., cov: 33)

Exomes 𝑓: 0.0050 ( 67 hom. )

Consequence

MFN2
NM_014874.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: 0.897

Publications

18 publications found

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]

MFN2 Gene-Disease associations (from GenCC):

neuropathy, hereditary motor and sensory, type 6A
Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
Charcot-Marie-Tooth disease, axonal, autosomal recessive, type 2a2b;
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
axonal hereditary motor and sensory neuropathy
Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen
Charcot-Marie-Tooth disease type 2A2
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
hereditary motor and sensory neuropathy type 6
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
multiple symmetric lipomatosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
severe early-onset axonal neuropathy due to MFN2 deficiency
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

MFN2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -17 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, 9 uncertain in NM_014874.4

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, Charcot-Marie-Tooth disease, axonal, autosomal recessive, type 2a2b;, severe early-onset axonal neuropathy due to MFN2 deficiency, hereditary motor and sensory neuropathy type 6, axonal hereditary motor and sensory neuropathy, multiple symmetric lipomatosis, neuropathy, hereditary motor and sensory, type 6A.

BP4

Computational evidence support a benign effect (MetaRNN=0.0077108443).

BP6

Variant 1-12009635-G-A is Benign according to our data. Variant chr1-12009635-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 138217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00586 (892/152288) while in subpopulation NFE AF = 0.00447 (304/68022). AF 95% confidence interval is 0.00406. There are 14 homozygotes in GnomAd4. There are 582 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 14 AD,AR,SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MFN2	NM_014874.4 link	c.2113G>A	p.Val705Ile	missense_variant	Exon 18 of 19	ENST00000235329.10	NP_055689.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MFN2	ENST00000235329.10 link	c.2113G>A	p.Val705Ile	missense_variant	Exon 18 of 19	1	NM_014874.4	ENSP00000235329.5

Frequencies

GnomAD3 genomes

AF:

0.00586

AC:

892

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000700

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00255

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.0475

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00447

Gnomad OTH

AF:

0.00334

GnomAD2 exomes

AF:

0.00658

AC:

1656

AN:

251486

AF XY:

0.00667

show subpopulations

Gnomad AFR exome

AF:

0.000492

Gnomad AMR exome

AF:

0.000405

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0444

Gnomad NFE exome

AF:

0.00501

Gnomad OTH exome

AF:

0.00782

GnomAD4 exome

AF:

0.00499

AC:

7301

AN:

1461876

Hom.:

Cov.:

AF XY:

0.00492

AC XY:

3581

AN XY:

727234

show subpopulations

African (AFR)

AF:

0.000329

AC:

AN:

33480

American (AMR)

AF:

0.000671

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000115

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00169

AC:

146

AN:

86258

European-Finnish (FIN)

AF:

0.0416

AC:

2220

AN:

53416

Middle Eastern (MID)

AF:

0.00277

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00413

AC:

4592

AN:

1111998

Other (OTH)

AF:

0.00469

AC:

283

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

467

934

1402

1869

2336

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

160

320

480

640

800

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00586

AC:

892

AN:

152288

Hom.:

Cov.:

AF XY:

0.00782

AC XY:

582

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.000698

AC:

AN:

41544

American (AMR)

AF:

0.00255

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00124

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0475

AC:

504

AN:

10610

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00447

AC:

304

AN:

68022

Other (OTH)

AF:

0.00331

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

134

179

224

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00402

Hom.:

Bravo

AF:

0.00264

TwinsUK

AF:

0.00485

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00384

AC:

ExAC

AF:

0.00635

AC:

771

EpiCase

AF:

0.00349

EpiControl

AF:

0.00403

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

MFN2: BS2 -

Mar 29, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 05, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:4

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 12, 2013

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Aug 15, 2018

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Charcot-Marie-Tooth disease type 2

Benign:2

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Charcot-Marie-Tooth disease

Benign:1

Molecular Genetics Laboratory, London Health Sciences Centre

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary motor and sensory neuropathy with optic atrophy

Benign:1

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Charcot-Marie-Tooth disease, axonal, autosomal recessive, type 2a2b;;C4721887:Charcot-Marie-Tooth disease type 2A2;CN305336:Neuropathy, hereditary motor and sensory, type 6A

Benign:1

Feb 23, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.30

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.36

T;T

Eigen

Benign

-0.52

Eigen_PC

Benign

-0.41

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.65

T;.

MetaRNN

Benign

0.0077

T;T

MetaSVM

Uncertain

-0.13

MutationAssessor

Benign

0.93

L;L

PhyloP100

0.90

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.54

N;N

REVEL

Benign

0.17

Sift

Benign

0.40

T;T

Sift4G

Benign

0.19

T;T

Polyphen

0.026

B;B

Vest4

0.20

MVP

0.45

MPC

0.18

ClinPred

0.0095

GERP RS

2.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.011

gMVP

0.24

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over