1-12011547-C-G

Variant names:

• chr1-12011547-C-G
• rs863224968
• NM_014874.4:c.2256C>G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_014874.4(MFN2):​c.2256C>G​(p.Tyr752*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. Y752Y) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MFN2 NM_014874.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.13

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 4 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-12011547-C-G is Pathogenic according to our data. Variant chr1-12011547-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 240946.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MFN2	NM_014874.4	c.2256C>G	p.Tyr752*	stop_gained	Exon 19 of 19	ENST00000235329.10	NP_055689.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MFN2	ENST00000235329.10	c.2256C>G	p.Tyr752*	stop_gained	Exon 19 of 19	1	NM_014874.4	ENSP00000235329.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Charcot-Marie-Tooth disease type 2 Pathogenic:1

Jan 16, 2016

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change results in a premature translational stop signal in the last exon of the MFN2 mRNA at codon 752 (p.Tyr752*). While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated MFN2 protein. This variant is not present in population databases (ExAC no frequency). While this particular nucleotide change has not been reported in the literature, a different nucleotide change c.2256C>A causing the same p.Tyr752* truncation has been reported in a patient affected with CMT2A (PMID: 21508331). This variant is expected to interfere with MFN2 protein function because it disrupts a highly conserved coiled-coil region which is essential for tethering of mitochondria before fusion (PMID: 21508331). In summary, this sequence change is predicted to produce a truncated protein product which disrupts a highly conserved functional region of the MFN2 protein. While this variant is novel at the nucleotide level, the same protein truncation has been reported in a patient affected with CMT2A. For these reasons, it has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	40
DANN	Uncertain	1.0
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.96	D
Vest4		0.77
GERP RS		4.5

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

LitVar

Other links and lift over

dbSNP: rs863224968; hg19: chr1-12071604;