rs119103267

Variant names:

• chr1-12009641-C-T
• rs119103267
• NM_014874.4:c.2119C>T
• MFN2 p.Arg707Trp

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+5 Uncertain · Hot

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 5 classification points (ACGS-UK Somatic Oncogenicity v2025). O1_ModerateO5_SupportingO6_SupportingO8_Supporting

The NM_014874.4(MFN2):c.2119C>T (p.Arg707Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The gene MFN2 is a tumor suppressor gene (CancerMine: 7 TSG, 2 oncogene, 1 driver citations). The gene MFN2 is a known oncogene (CancerMine: 7 TSG, 2 oncogene, 1 driver citations). The gene MFN2 is a cancer driver gene (CancerMine: 7 TSG, 2 oncogene, 1 driver citations). The variant allele was found at a cumulative frequency of 0.000453 (AC=731) in the gnomAD database across 1,614,174 control chromosomes, including 1 homozygote. The grpmax filtering allele frequency (95% CI) is 0.000546. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000803475: Well-established functional studies show a deleterious effect (PMID:26085578)." and additional evidence is available in ClinVar. A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.R707P: Likely_pathogenic (ClinVar VariationId 637750, 1 star) Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.R707?: Uncertain_significance (ClinVar VariationId 917375, 1 star); p.R707Q: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 1806999) This exact variant is curated in the UniProt human variants database as Uncertain Significance; it is also listed as a COSMIC curated somatic variant.

• Frequency:
  • Genomes: 𝑓 0.00027 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00047 (1 hom.)
• Consequence: MFN2 NM_014874.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:32 O:2
• Conservation: PhyloP100: 2.89
• Publications: 55 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):

• Charcot-Marie-Tooth disease type 2A2

  Inheritance: AD, SD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen
• 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: G2P, Labcorp Genetics (formerly Invitae)
• multiple symmetric lipomatosis with partial lipodystrophy

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, ClinGen
• hereditary motor and sensory neuropathy

  Inheritance: SD Classification: STRONG Submitted by: PanelApp Australia
• 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

Classification according to ACGS-UK Somatic Oncogenicity v2025

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 5 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O1Established oncogenic variant		TSG gene: ClinVar germline P/LP ★★+ — Moderate (O1); O1 contributing sources (2.0 pts): ClinVar germline P/LP in TSG (★★)
	O5Same location/impact as known oncogenic		Different AA at same residue with oncogenic evidence (or germline P/LP in TSG), or same AA change SCI Tier II Potential — Supporting (O5); ClinVar same-AA oncogenic/T1: false | ClinVar same-AA SCI tier: — | CGI same-AA oncogenic: false | TSG: true | ClinVar same-AA germline P/LP: false | CIViC LOF: false | ClinVar diff-AA oncogenic: false | ClinVar diff-AA germline P/LP: true
	O6Computational evidence supports deleterious effect		Computational evidence supports a deleterious/oncogenic effect; Missense variant — primary computational scorer supports an oncogenic/deleterious effect
	O8Missense constraint in gene or region		Missense in gene/domain constrained for missense variation where missense is common disease mechanism (O8 supporting); Gene/disease mechanism: missense is a common mechanism of oncogenesis; gnomAD missense Z-score: 3.23 (threshold ≥3.09 for constraint)

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_014874.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	MFN2 NM_014874.4	MANE Select	c.2119C>T p.Arg707Trp	missense	Exon 18 of 19	Prot: NP_055689.1 UniProt:
	MFN2 NM_001127660.2		c.2119C>T p.Arg707Trp	missense	Exon 17 of 18	Prot: NP_001121132.1 UniProt:

MFN2 NM_014874.4

MANE Select

HGVSc / HGVSpc.2119C>Tp.Arg707Trp

Exon rankExon 18 of 19

missense

Prot: NP_055689.1UniProt: O95140-1

MFN2 NM_001127660.2

HGVSc / HGVSpc.2119C>Tp.Arg707Trp

Exon rankExon 17 of 18

missense

Prot: NP_001121132.1UniProt: O95140-1

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	MFN2 ENST00000235329.10	TSL:1MANE Select	c.2119C>T p.Arg707Trp	missense	Exon 18 of 19	Prot: ENSP00000235329.5 UniProt:
	MFN2 ENST00000675298.1		c.2119C>T p.Arg707Trp	missense	Exon 18 of 19	Prot: ENSP00000501839.1 UniProt:
	MFN2 ENST00000675817.1		c.2251C>T p.Arg751Trp	missense	Exon 19 of 20	Prot: ENSP00000502422.1 UniProt:

MFN2 ENST00000235329.10

TSL:1MANE Select

HGVSc / HGVSpc.2119C>Tp.Arg707Trp

Exon rankExon 18 of 19

missense

Prot: ENSP00000235329.5UniProt: O95140-1

MFN2 ENST00000675298.1

HGVSc / HGVSpc.2119C>Tp.Arg707Trp

Exon rankExon 18 of 19

missense

Prot: ENSP00000501839.1UniProt: A0A6Q8PFJ4

MFN2 ENST00000675817.1

HGVSc / HGVSpc.2251C>Tp.Arg751Trp

Exon rankExon 19 of 20

missense

Prot: ENSP00000502422.1UniProt: A0A6Q8PGV8

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.000269	AC:41	Hom:0	AN:152168	Cov:33
GnomAD2 exomes	AF: 0.000251	AC:63	Hom:	AN:251494	Cov:
GnomAD4 exome	AF: 0.000472	AC:690	Hom:1	AN:1461888	Cov:31
GnomAD4 genome	AF: 0.000269	AC:41	Hom:0	AN:152286	Cov:33
TOPMed (Bravo)	AF: 0.000246	AC:65	Hom:0	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.000347	AC:174	Hom:0	AN:500896	Cov:
Local & regional cohorts 6 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.000427	AC:1	Hom:0	AN:2342	Cov:
ESP6500 (Exome Variant Server)	AF: 0.000384	AC:5	Hom:	AN:13006	Cov:
Korea4K (4,157 Koreans)	AF: 0.000138	AC:1	Hom:	AN:7234	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.00	AC:0	Hom:0	AN:122370	Cov:
Turkish Variome	AF: 0.000647	AC:1	Hom:0	AN:1546	Cov:
UK10K	AF: 0.000397	AC:3	Hom:	AN:7562	Cov:

Showing 12 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.00108 *	12	11112	0.000908 *	16	17618
BipEx(Bipolar disorder (including schizoaffective))	0.000563	16	28420	0.000589	17	28844
Epi25(Epilepsy)	0.000358	15	41958	0.000314	21	66888
SCHEMA(Schizophrenia)	0.000152	18	118122	0.000227	42	184806

Showing 4 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
8	-	-	not provided (8)
5	-	-	Charcot-Marie-Tooth disease, axonal, autosomal recessive, type 2a2b; (5)
4	-	-	Charcot-Marie-Tooth disease type 2A2 (4)
3	-	-	MFN2-related disorder (3)
2	-	-	Charcot-Marie-Tooth disease, axonal, autosomal recessive, type 2a2b;;C4721887:Charcot-Marie-Tooth disease type 2A2;CN305336:Neuropathy, hereditary motor and sensory, type 6A (2)
1	-	-	Charcot-Marie-Tooth disease (1)
1	-	-	Charcot-Marie-Tooth disease type 2 (1)
1	-	-	Charcot-Marie-Tooth disease, axonal, autosomal recessive, type 2a2b;;C4721887:Charcot-Marie-Tooth disease type 2A2 (2)
1	-	-	Inborn genetic diseases (1)
1	-	-	Multiple symmetric lipomatosis (1)
1	-	-	Multiple symmetric lipomatosis;C4310725:Charcot-Marie-Tooth disease, axonal, autosomal recessive, type 2a2b; (1)
1	-	-	Neuropathy, hereditary motor and sensory, type 6A (1)
1	-	-	Peripheral axonal neuropathy (1)
1	-	-	Semidominant MFN2-related disorders (1)
1	-	-	Tip-toe gait (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	24
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.79	D
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.90	D
GPN-Star LLR	N/A	-8.2
GPN-Star score	N/A	8.2
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Pathogenic	1.0	D
Mutation Taster	N/A	22/78	disease causing (ClinVar)
MutationAssessor	Benign	1.4	L
PhyloP100	Benign	2.9
popEVE	Benign	-3.5
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-2.8	D
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.7
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.013	D
Varity_R	N/A	0.60
VESM-3B	Benign	-9.3

Showing 29 of 29 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.010
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs119103267;

hg19: chr1-12069698;

COSMIC: COSV104580923;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar