chr1-11980267-A-G

Variant names:

Variant summary

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

The ENST00000676426.1(MFN2):n.-367A>G variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.488 in 397,472 control chromosomes in the GnomAD database, including 48,847 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.51 ( 20267 hom., cov: 32)

Exomes 𝑓: 0.48 ( 28580 hom. )

Consequence

MFN2
ENST00000676426.1 non_coding_transcript_exon

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.901

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: 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:

ENSG00000287384 (HGNC:):

ENSG00000287384 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 1-11980267-A-G is Benign according to our data. Variant chr1-11980267-A-G is described in ClinVar as [Benign]. Clinvar id is 292362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.622 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MFN2	NM_014874.4 link	c.-367A>G		upstream_gene_variant		ENST00000235329.10	NP_055689.1	O95140-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MFN2	ENST00000235329.10 link	c.-367A>G		upstream_gene_variant		1	NM_014874.4	ENSP00000235329.5		O95140-1

Frequencies

GnomAD3 genomes

AF:

0.507

AC:

76910

AN:

151808

Hom.:

20255

Cov.:

show subpopulations

Gnomad AFR

AF:

0.611

Gnomad AMI

AF:

0.246

Gnomad AMR

AF:

0.430

Gnomad ASJ

AF:

0.324

Gnomad EAS

AF:

0.640

Gnomad SAS

AF:

0.624

Gnomad FIN

AF:

0.563

Gnomad MID

AF:

0.392

Gnomad NFE

AF:

0.447

Gnomad OTH

AF:

0.484

GnomAD4 exome

AF:

0.476

AC:

116973

AN:

245546

Hom.:

28580

Cov.:

AF XY:

0.474

AC XY:

58964

AN XY:

124502

show subpopulations

African (AFR)

AF:

0.607

AC:

4336

AN:

7138

American (AMR)

AF:

0.457

AC:

3378

AN:

7392

Ashkenazi Jewish (ASJ)

AF:

0.335

AC:

3081

AN:

9202

East Asian (EAS)

AF:

0.584

AC:

13358

AN:

22862

South Asian (SAS)

AF:

0.631

AC:

1909

AN:

3026

European-Finnish (FIN)

AF:

0.577

AC:

12017

AN:

20812

Middle Eastern (MID)

AF:

0.413

AC:

534

AN:

1292

European-Non Finnish (NFE)

AF:

0.447

AC:

70426

AN:

157514

Other (OTH)

AF:

0.487

AC:

7934

AN:

16308

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

3193

6387

9580

12774

15967

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.507

AC:

76969

AN:

151926

Hom.:

20267

Cov.:

AF XY:

0.512

AC XY:

38018

AN XY:

74246

show subpopulations

African (AFR)

AF:

0.611

AC:

25306

AN:

41450

American (AMR)

AF:

0.430

AC:

6567

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.324

AC:

1122

AN:

3468

East Asian (EAS)

AF:

0.640

AC:

3293

AN:

5144

South Asian (SAS)

AF:

0.623

AC:

3005

AN:

4820

European-Finnish (FIN)

AF:

0.563

AC:

5937

AN:

10542

Middle Eastern (MID)

AF:

0.388

AC:

114

AN:

294

European-Non Finnish (NFE)

AF:

0.447

AC:

30383

AN:

67904

Other (OTH)

AF:

0.483

AC:

1019

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

1941

3883

5824

7766

9707

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.444

Hom.:

5286

Bravo

AF:

0.496

Asia WGS

AF:

0.641

AC:

2229

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jun 29, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Charcot-Marie-Tooth disease type 2

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary motor and sensory neuropathy with optic atrophy

Benign:1

Jan 12, 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. -

Ehlers-Danlos syndrome, kyphoscoliotic type 1

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary motor and sensory neuropathy

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

1.5

(source)

DANN

Benign

0.52

PhyloP100

-0.90

PromoterAI

-0.0087

Neutral

(source)

Mutation Taster

=298/2

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

chr1-11980267-A-G

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