rs77262016

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_014874.4(MFN2):c.2204+15T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0606 in 1,614,036 control chromosomes in the GnomAD database, including 3,451 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.076 ( 541 hom., cov: 33)

Exomes 𝑓: 0.059 ( 2910 hom. )

Consequence

MFN2
NM_014874.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.0510

Publications

8 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: G2P, Labcorp Genetics (formerly Invitae)
multiple symmetric lipomatosis with partial lipodystrophy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BP6

Variant 1-12009741-T-C is Benign according to our data. Variant chr1-12009741-T-C is described in ClinVar as Benign. ClinVar VariationId is 138218.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.12 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MFN2	NM_014874.4	MANE Select	c.2204+15T>C		intron	N/A	NP_055689.1	O95140-1
	MFN2	NM_001127660.2		c.2204+15T>C		intron	N/A	NP_001121132.1	O95140-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
MFN2	ENST00000235329.10	TSL:1 MANE Select	c.2204+15T>C	intron	N/A	ENSP00000235329.5	O95140-1
MFN2	ENST00000675298.1		c.2204+15T>C	intron	N/A	ENSP00000501839.1	A0A6Q8PFJ4
MFN2	ENST00000675817.1		c.2336+15T>C	intron	N/A	ENSP00000502422.1	A0A6Q8PGV8

Frequencies

GnomAD3 genomes

AF:

0.0756

AC:

11502

AN:

152190

Hom.:

541

Cov.:

show subpopulations

Gnomad AFR

AF:

0.122

Gnomad AMI

AF:

0.0647

Gnomad AMR

AF:

0.0544

Gnomad ASJ

AF:

0.0893

Gnomad EAS

AF:

0.125

Gnomad SAS

AF:

0.0754

Gnomad FIN

AF:

0.0177

Gnomad MID

AF:

0.0633

Gnomad NFE

AF:

0.0570

Gnomad OTH

AF:

0.0635

GnomAD2 exomes

AF:

0.0623

AC:

15618

AN:

250890

AF XY:

0.0625

show subpopulations

Gnomad AFR exome

AF:

0.129

Gnomad AMR exome

AF:

0.0290

Gnomad ASJ exome

AF:

0.0895

Gnomad EAS exome

AF:

0.129

Gnomad FIN exome

AF:

0.0158

Gnomad NFE exome

AF:

0.0547

Gnomad OTH exome

AF:

0.0527

GnomAD4 exome

AF:

0.0590

AC:

86272

AN:

1461728

Hom.:

2910

Cov.:

AF XY:

0.0587

AC XY:

42710

AN XY:

727188

show subpopulations

African (AFR)

AF:

0.124

AC:

4145

AN:

33478

American (AMR)

AF:

0.0313

AC:

1401

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0847

AC:

2213

AN:

26136

East Asian (EAS)

AF:

0.103

AC:

4107

AN:

39694

South Asian (SAS)

AF:

0.0732

AC:

6316

AN:

86254

European-Finnish (FIN)

AF:

0.0154

AC:

823

AN:

53352

Middle Eastern (MID)

AF:

0.0447

AC:

258

AN:

5766

European-Non Finnish (NFE)

AF:

0.0567

AC:

63054

AN:

1111936

Other (OTH)

AF:

0.0655

AC:

3955

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

4860

9720

14581

19441

24301

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2512

5024

7536

10048

12560

<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:

0.0757

AC:

11523

AN:

152308

Hom.:

541

Cov.:

AF XY:

0.0745

AC XY:

5549

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.122

AC:

5090

AN:

41560

American (AMR)

AF:

0.0542

AC:

830

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0893

AC:

310

AN:

3472

East Asian (EAS)

AF:

0.125

AC:

648

AN:

5186

South Asian (SAS)

AF:

0.0756

AC:

365

AN:

4826

European-Finnish (FIN)

AF:

0.0177

AC:

188

AN:

10620

Middle Eastern (MID)

AF:

0.0578

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0570

AC:

3878

AN:

68020

Other (OTH)

AF:

0.0652

AC:

138

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

555

1110

1665

2220

2775

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

126

252

378

504

630

<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:

0.0663

Hom.:

Bravo

AF:

0.0796

Asia WGS

AF:

0.103

AC:

360

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Charcot-Marie-Tooth disease type 2 (2)

not specified (2)

Charcot-Marie-Tooth disease (1)

Hereditary motor and sensory neuropathy with optic atrophy (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

6.0

(source)

DANN

Benign

0.45

PhyloP100

-0.051

Mutation Taster

=100/0

polymorphism (auto)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over