chr1-12009741-T-C

Variant names:

• chr1-12009741-T-C
• rs77262016
• NM_014874.4:c.2204+15T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.0510
• Publications: 8 publications found

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

ACMG classification

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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MFN2	NM_014874.4	c.2204+15T>C		intron_variant	Intron 18 of 18	ENST00000235329.10	NP_055689.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MFN2	ENST00000235329.10	c.2204+15T>C		intron_variant	Intron 18 of 18	1	NM_014874.4	ENSP00000235329.5

Frequencies

GnomAD3 genomes AF: 0.0756 AC: 11502 AN: 152190 Hom.: 541 Cov.: 33

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

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.: 32 AF XY: 0.0587 AC XY: 42710 AN XY: 727188

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

GnomAD4 genome AF: 0.0757 AC: 11523 AN: 152308 Hom.: 541 Cov.: 33 AF XY: 0.0745 AC XY: 5549 AN XY: 74474

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: 17 AN: 294

European-Non Finnish (NFE) AF: 0.0570 AC: 3878 AN: 68020

Other (OTH) AF: 0.0652 AC: 138 AN: 2116

Alfa AF: 0.0663 Hom.: 81

Bravo AF: 0.0796

Asia WGS AF: 0.103 AC: 360 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

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

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. -

Feb 03, 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

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. -

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	-0.86
CADD	Benign	6.0
DANN	Benign	0.45
PhyloP100		-0.051
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs77262016; hg19: chr1-12069798;