rs387906990

chr1-11998817-T-C

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_014874.4(MFN2):c.647T>C(p.Phe216Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000254 in 1,614,024 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000024 (0 hom.)
• Consequence: MFN2 NM_014874.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.58

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.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_014874.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, MFN2
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.963
• PP5: Variant 1-11998817-T-C is Pathogenic according to our data. Variant chr1-11998817-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 30736.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-11998817-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MFN2	NM_014874.4	c.647T>C	p.Phe216Ser	missense_variant	7/19	ENST00000235329.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MFN2	ENST00000235329.10	c.647T>C	p.Phe216Ser	missense_variant	7/19	1	NM_014874.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152130 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251496 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135922

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000239 AC: 35 AN: 1461894 Hom.: 0 Cov.: 32 AF XY: 0.0000165 AC XY: 12 AN XY: 727248

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: 0.0000297

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152130 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74334

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000688 Hom.: 0

Bravo AF: 0.0000453

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 18, 2015	The F216S variant has been previously reported as a homozygous variant in a patient with early onset hereditary motor and sensory neuropathy; the parents were unaffected carriers of the F216S variant, suggesting autosomal recessive inheritance (Vallat et al., 2008). F216S was subsequently reported in two siblings with early onset CMT2 who both had a second MFN2 variant on the opposite allele; the mother was an unaffected carrier of the F216S variant (Polke et al., 2011). F216S was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. It is a non-conservative amino acid substitution that occurs at a highly conserved position in the protein. Missense variant in nearby residues (T206I, I213T, D214N, F223L) have been reported in the Human Gene Mutation Database in association with neuropathy (Stenson et al., 2014), supporting the functional importance of this region of the protein. -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 22, 2017	- -

Charcot-Marie-Tooth disease, axonal, autosomal recessive, type 2a2b; Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 12, 2011

- -

Charcot-Marie-Tooth disease type 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 11, 2023

This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 216 of the MFN2 protein (p.Phe216Ser). This variant is present in population databases (rs387906990, gnomAD 0.002%). This missense change has been observed in individual(s) with Charcot-Marie-Tooth disease (PMID: 18957892, 21715711, 23147504, 26114802). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 30736). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MFN2 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.46
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D;D
Eigen	Benign	0.032
Eigen_PC	Benign	0.19
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;.
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Uncertain	0.49	D
MutationAssessor	Benign	0.94	L;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-3.2	D;D
REVEL	Pathogenic	0.79
Sift	Benign	0.13	T;T
Sift4G	Uncertain	0.059	T;T
Polyphen		0.045	B;B
Vest4		0.91
MutPred		0.89		Loss of stability (P = 0.0098);Loss of stability (P = 0.0098);
MVP		0.99
MPC		1.3
ClinPred		0.88	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.75
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs387906990; hg19: chr1-12058874;