rs369762154

Variant names:

• chr1-12007167-C-T
• rs369762154
• NM_014874.4:c.1987C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-12007167-C-T
• chr1-12007167-C-G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP2

The NM_014874.4(MFN2):​c.1987C>T​(p.Arg663Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000138 in 1,614,192 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R663H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: MFN2 NM_014874.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:6 B:2
• Conservation: PhyloP100: 0.782
• Publications: 7 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):

• 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 Submitted by: ClinGen
• axonal hereditary motor and sensory neuropathy

  Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen
• Charcot-Marie-Tooth disease type 2A2

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• 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, axonal, autosomal recessive, type 2a2b;, multiple symmetric lipomatosis, Charcot-Marie-Tooth disease type 2A2, axonal hereditary motor and sensory neuropathy, neuropathy, hereditary motor and sensory, type 6A, multiple symmetric lipomatosis with partial lipodystrophy, severe early-onset axonal neuropathy due to MFN2 deficiency, hereditary motor and sensory neuropathy type 6.

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MFN2	NM_014874.4	MANE Select	c.1987C>T	p.Arg663Cys	missense	Exon 17 of 19	NP_055689.1	O95140-1
	MFN2	NM_001127660.2		c.1987C>T	p.Arg663Cys	missense	Exon 16 of 18	NP_001121132.1	O95140-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MFN2	ENST00000235329.10	TSL:1 MANE Select	c.1987C>T	p.Arg663Cys	missense	Exon 17 of 19	ENSP00000235329.5	O95140-1
	MFN2	ENST00000675298.1		c.1987C>T	p.Arg663Cys	missense	Exon 17 of 19	ENSP00000501839.1	A0A6Q8PFJ4
	MFN2	ENST00000675817.1		c.2119C>T	p.Arg707Cys	missense	Exon 18 of 20	ENSP00000502422.1	A0A6Q8PGV8

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 152246 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000175 AC: 44 AN: 251412 AF XY: 0.000213

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00188

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000137 AC: 201 AN: 1461828 Hom.: 0 Cov.: 33 AF XY: 0.000164 AC XY: 119 AN XY: 727228

African (AFR) AF: 0.0000597 AC: 2 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00256 AC: 67 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000348 AC: 30 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53356

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.0000764 AC: 85 AN: 1112010

Other (OTH) AF: 0.000248 AC: 15 AN: 60396

GnomAD4 genome AF: 0.000144 AC: 22 AN: 152364 Hom.: 0 Cov.: 33 AF XY: 0.000175 AC XY: 13 AN XY: 74498

African (AFR) AF: 0.00 AC: 0 AN: 41600

American (AMR) AF: 0.00 AC: 0 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00317 AC: 11 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.0000708 Hom.: 0

Bravo AF: 0.000113

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000132 AC: 16

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	-	not provided (3)
-	-	2	Charcot-Marie-Tooth disease type 2 (2)
1	1	-	Charcot-Marie-Tooth disease type 2A2 (2)
-	1	-	Hereditary motor and sensory neuropathy with optic atrophy (1)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.92	D
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.35	D
MetaRNN	Uncertain	0.70	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.9	L
PhyloP100		0.78
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-5.3	D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0080	D
Polyphen		1.0	D
Vest4		0.89
MVP		0.98
MPC		0.92
ClinPred		0.31	T
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.60
gMVP		0.57
Mutation Taster		=55/45	polymorphism

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

Other links and lift over

dbSNP: rs369762154; hg19: chr1-12067224;