1-12002304-C-G

Variant names:

• chr1-12002304-C-G
• rs2236058
• NM_014874.4:c.1160+201C>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_014874.4(MFN2):​c.1160+201C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.574 in 152,166 control chromosomes in the GnomAD database, including 25,492 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.57 (25492 hom., cov: 34)
• Consequence: MFN2 NM_014874.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0370
• Publications: 17 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 1-12002304-C-G is Benign according to our data. Variant chr1-12002304-C-G is described in ClinVar as Benign. ClinVar VariationId is 683181.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.614 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MFN2	NM_014874.4	c.1160+201C>G		intron_variant	Intron 11 of 18	ENST00000235329.10	NP_055689.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MFN2	ENST00000235329.10	c.1160+201C>G		intron_variant	Intron 11 of 18	1	NM_014874.4	ENSP00000235329.5

Frequencies

GnomAD3 genomes AF: 0.574 AC: 87266 AN: 152048 Hom.: 25486 Cov.: 34

Gnomad AFR AF: 0.528

Gnomad AMI AF: 0.424

Gnomad AMR AF: 0.499

Gnomad ASJ AF: 0.412

Gnomad EAS AF: 0.555

Gnomad SAS AF: 0.633

Gnomad FIN AF: 0.709

Gnomad MID AF: 0.557

Gnomad NFE AF: 0.606

Gnomad OTH AF: 0.569

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.574 AC: 87315 AN: 152166 Hom.: 25492 Cov.: 34 AF XY: 0.575 AC XY: 42784 AN XY: 74386

African (AFR) AF: 0.528 AC: 21912 AN: 41520

American (AMR) AF: 0.499 AC: 7625 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.412 AC: 1428 AN: 3470

East Asian (EAS) AF: 0.555 AC: 2873 AN: 5174

South Asian (SAS) AF: 0.633 AC: 3053 AN: 4824

European-Finnish (FIN) AF: 0.709 AC: 7502 AN: 10588

Middle Eastern (MID) AF: 0.544 AC: 160 AN: 294

European-Non Finnish (NFE) AF: 0.606 AC: 41173 AN: 67976

Other (OTH) AF: 0.569 AC: 1202 AN: 2114

Alfa AF: 0.586 Hom.: 3144

Bravo AF: 0.554

Asia WGS AF: 0.600 AC: 2085 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 19, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	4.0
DANN	Benign	0.65
PhyloP100		0.037
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: rs2236058; hg19: chr1-12062361;