chr1-12005784-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_014874.4(MFN2):c.1569C>T(p.Ser523Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0552 in 1,614,182 control chromosomes in the GnomAD database, including 2,840 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.047 ( 234 hom., cov: 33)

Exomes 𝑓: 0.056 ( 2606 hom. )

Consequence

MFN2
NM_014874.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.654

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 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=-0.4).

BP6

Variant 1-12005784-C-T is Benign according to our data. Variant chr1-12005784-C-T is described in ClinVar as [Benign]. Clinvar id is 138215.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-12005784-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=0.654 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.118 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MFN2	NM_014874.4 link	c.1569C>T	p.Ser523Ser	synonymous_variant	Exon 15 of 19	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.1569C>T	p.Ser523Ser	synonymous_variant	Exon 15 of 19	1	NM_014874.4	ENSP00000235329.5		O95140-1

Frequencies

GnomAD3 genomes

AF:

0.0468

AC:

7128

AN:

152202

Hom.:

233

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0234

Gnomad AMI

AF:

0.0647

Gnomad AMR

AF:

0.0419

Gnomad ASJ

AF:

0.0815

Gnomad EAS

AF:

0.126

Gnomad SAS

AF:

0.0751

Gnomad FIN

AF:

0.0177

Gnomad MID

AF:

0.0633

Gnomad NFE

AF:

0.0567

Gnomad OTH

AF:

0.0460

GnomAD2 exomes

AF:

0.0545

AC:

13696

AN:

251496

AF XY:

0.0570

show subpopulations

Gnomad AFR exome

AF:

0.0228

Gnomad AMR exome

AF:

0.0236

Gnomad ASJ exome

AF:

0.0834

Gnomad EAS exome

AF:

0.132

Gnomad FIN exome

AF:

0.0159

Gnomad NFE exome

AF:

0.0545

Gnomad OTH exome

AF:

0.0492

GnomAD4 exome

AF:

0.0561

AC:

82027

AN:

1461862

Hom.:

2606

Cov.:

AF XY:

0.0563

AC XY:

40951

AN XY:

727236

show subpopulations

African (AFR)

AF:

0.0231

AC:

775

AN:

33480

American (AMR)

AF:

0.0255

AC:

1140

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0795

AC:

2078

AN:

26136

East Asian (EAS)

AF:

0.105

AC:

4175

AN:

39700

South Asian (SAS)

AF:

0.0733

AC:

6319

AN:

86258

European-Finnish (FIN)

AF:

0.0155

AC:

827

AN:

53420

Middle Eastern (MID)

AF:

0.0425

AC:

245

AN:

5766

European-Non Finnish (NFE)

AF:

0.0566

AC:

62910

AN:

1111984

Other (OTH)

AF:

0.0589

AC:

3558

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

4937

9874

14812

19749

24686

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0468

AC:

7133

AN:

152320

Hom.:

234

Cov.:

AF XY:

0.0470

AC XY:

3504

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.0235

AC:

976

AN:

41576

American (AMR)

AF:

0.0418

AC:

640

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0815

AC:

283

AN:

3472

East Asian (EAS)

AF:

0.126

AC:

655

AN:

5194

South Asian (SAS)

AF:

0.0756

AC:

365

AN:

4828

European-Finnish (FIN)

AF:

0.0177

AC:

188

AN:

10618

Middle Eastern (MID)

AF:

0.0578

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0567

AC:

3855

AN:

68022

Other (OTH)

AF:

0.0450

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

344

687

1031

1374

1718

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0502

Hom.:

102

Bravo

AF:

0.0469

Asia WGS

AF:

0.0910

AC:

317

AN:

3478

EpiCase

AF:

0.0567

EpiControl

AF:

0.0609

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 24, 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. -

Charcot-Marie-Tooth disease type 2

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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. -

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

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Benign

0.83

PhyloP100

0.65

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

Loading publications...

chr1-12005784-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over