Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_014874.4(MFN2):c.165C>T(p.Thr55Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0019 in 1,614,010 control chromosomes in the GnomAD database, including 57 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0018 ( 8 hom., cov: 32)

Exomes 𝑓: 0.0019 ( 49 hom. )

Consequence

MFN2
NM_014874.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -1.28

Publications

6 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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.44).

BP6

Variant 1-11989333-C-T is Benign according to our data. Variant chr1-11989333-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 138220.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.28 with no splicing effect.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00183 (279/152212) while in subpopulation EAS AF = 0.0421 (218/5180). AF 95% confidence interval is 0.0375. There are 8 homozygotes in GnomAd4. There are 162 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 8 AD,AR,SD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014874.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MFN2	NM_014874.4	MANE Select	c.165C>T	p.Thr55Thr	synonymous	Exon 3 of 19	NP_055689.1
	MFN2	NM_001127660.2		c.165C>T	p.Thr55Thr	synonymous	Exon 2 of 18	NP_001121132.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MFN2	ENST00000235329.10	TSL:1 MANE Select	c.165C>T	p.Thr55Thr	synonymous	Exon 3 of 19	ENSP00000235329.5
MFN2	ENST00000675298.1		c.165C>T	p.Thr55Thr	synonymous	Exon 3 of 19	ENSP00000501839.1
MFN2	ENST00000675817.1		c.165C>T	p.Thr55Thr	synonymous	Exon 3 of 20	ENSP00000502422.1

Frequencies

GnomAD3 genomes

AF:

0.00184

AC:

280

AN:

152094

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0422

Gnomad SAS

AF:

0.0112

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.00509

AC:

1280

AN:

251358

AF XY:

0.00581

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.0000867

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0445

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000528

Gnomad OTH exome

AF:

0.00147

GnomAD4 exome

AF:

0.00190

AC:

2781

AN:

1461798

Hom.:

Cov.:

AF XY:

0.00225

AC XY:

1633

AN XY:

727202

show subpopulations

African (AFR)

AF:

0.000119

AC:

AN:

33478

American (AMR)

AF:

0.000112

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0357

AC:

1416

AN:

39698

South Asian (SAS)

AF:

0.0132

AC:

1139

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53346

Middle Eastern (MID)

AF:

0.000867

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000279

AC:

AN:

1112004

Other (OTH)

AF:

0.00300

AC:

181

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

163

325

488

650

813

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

138

184

230

<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:

0.00183

AC:

279

AN:

152212

Hom.:

Cov.:

AF XY:

0.00218

AC XY:

162

AN XY:

74418

show subpopulations

African (AFR)

AF:

0.0000481

AC:

AN:

41542

American (AMR)

AF:

0.000131

AC:

AN:

15254

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.0421

AC:

218

AN:

5180

South Asian (SAS)

AF:

0.0112

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68026

Other (OTH)

AF:

0.00142

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

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:

0.000334

Hom.:

Bravo

AF:

0.00209

Asia WGS

AF:

0.0270

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Charcot-Marie-Tooth disease type 2 (2)

not provided (2)

not specified (2)

Charcot-Marie-Tooth disease (1)

Charcot-Marie-Tooth disease, axonal, autosomal recessive, type 2a2b;;C4721887:Charcot-Marie-Tooth disease type 2A2;CN305336:Neuropathy, hereditary motor and sensory, type 6A (1)

Hereditary motor and sensory neuropathy with optic atrophy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.44

CADD

Benign

9.5

(source)

DANN

Benign

0.68

PhyloP100

-1.3

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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rs77458527

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over