rs8192303

chr1-12004099-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_014874.4(MFN2):c.1268C>T(p.Thr423Met) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,812 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T423A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: MFN2 NM_014874.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.80

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, MFN2

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MFN2	NM_014874.4	c.1268C>T	p.Thr423Met	missense_variant	12/19	ENST00000235329.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MFN2	ENST00000235329.10	c.1268C>T	p.Thr423Met	missense_variant	12/19	1	NM_014874.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461812 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727222

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Charcot-Marie-Tooth disease type 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 13, 2020

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). This variant has not been reported in the literature in individuals with MFN2-related conditions. ClinVar contains an entry for this variant (Variation ID: 221059). This variant is not present in population databases (ExAC no frequency). This sequence change replaces threonine with methionine at codon 423 of the MFN2 protein (p.Thr423Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
Cadd	Pathogenic	29
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T;T
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D;.
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.74	D;D
MetaSVM	Uncertain	0.28	D
MutationAssessor	Uncertain	2.3	M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-2.0	N;N
REVEL	Uncertain	0.56
Sift	Uncertain	0.010	D;D
Sift4G	Uncertain	0.030	D;D
Polyphen		0.97	D;D
Vest4		0.73
MutPred		0.43		Loss of helix (P = 0.0104);Loss of helix (P = 0.0104);
MVP		0.83
MPC		0.61
ClinPred		0.96	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.14
gMVP		0.89

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: rs8192303; hg19: chr1-12064156; COSMIC: COSV99336578;