chr1-11998999-C-A

Variant names:

• chr1-11998999-C-A
• rs864622480
• NM_014874.4:c.720C>A

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PS1 PM1 PM2 PM5 PP2 PP3_Strong PP5_Moderate

The NM_014874.4(MFN2):​c.720C>A​(p.Phe240Leu) variant causes a missense 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 Likely pathogenic (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F240I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MFN2 NM_014874.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.22

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 Pathogenic. Variant got 17 ACMG points.

• PS1: Transcript NM_014874.4 (MFN2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 694947
• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_014874.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-11998997-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 567033.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant in the MFN2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 123 curated pathogenic missense variants (we use a threshold of 10). The gene has 23 curated benign missense variants. Gene score misZ: 1.6575 (below the threshold of 3.09). Trascript score misZ: 3.2174 (above the threshold of 3.09). GenCC associations: The gene is linked to Charcot-Marie-Tooth disease type 2A2, axonal hereditary motor and sensory neuropathy, hereditary motor and sensory neuropathy type 6, Charcot-Marie-Tooth disease, axonal, autosomal recessive, type 2a2b;, multiple symmetric lipomatosis, severe early-onset axonal neuropathy due to MFN2 deficiency.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.967
• PP5: Variant 1-11998999-C-A is Pathogenic according to our data. Variant chr1-11998999-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 220333.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-11998999-C-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MFN2	NM_014874.4	c.720C>A	p.Phe240Leu	missense_variant	Exon 8 of 19	ENST00000235329.10	NP_055689.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MFN2	ENST00000235329.10	c.720C>A	p.Phe240Leu	missense_variant	Exon 8 of 19	1	NM_014874.4	ENSP00000235329.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Charcot-Marie-Tooth disease type 2 Pathogenic:1

Sep 21, 2015

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Parental testing results indicate that this variant occurred de novo in this individual.  Approximately one third of CMT-associated MFN2 variants occur de novo (PMID: 24957169). In summary, the de novo and novel nature of this variant is consistent with it being pathogenic, however, functional or segregation data needed to fully establish this interpretation are not available.  For these reasons, this variant is classified as Likely Pathogenic. This sequence change replaces phenylalanine with leucine at codon 240 of the MFN2 protein (p.Phe240Leu). The phenylalanine residue is highly conserved and there is a small physicochemical difference between phenylalanine and leucine. This variant is not present in population databases and has not been published in the literature. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.42
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D;D
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Pathogenic	0.99	D;.
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Uncertain	0.55	D
MutationAssessor	Uncertain	2.2	M;M
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-5.6	D;D
REVEL	Pathogenic	0.80
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.94	P;P
Vest4		0.94
MutPred		0.83		Gain of ubiquitination at K238 (P = 0.1062);Gain of ubiquitination at K238 (P = 0.1062);
MVP		0.98
MPC		1.9
ClinPred		0.99	D
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs864622480; hg19: chr1-12059056;