chr1-12011376-C-T

Variant names:

• chr1-12011376-C-T
• rs3766741
• NM_014874.4:c.2205-120C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_014874.4(MFN2):​c.2205-120C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000115 in 1,046,816 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: MFN2 NM_014874.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.828
• Publications: 12 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: Labcorp Genetics (formerly Invitae), G2P
• 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MFN2	NM_014874.4	MANE Select	c.2205-120C>T		intron	N/A	NP_055689.1
	MFN2	NM_001127660.2		c.2205-120C>T		intron	N/A	NP_001121132.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MFN2	ENST00000235329.10	TSL:1 MANE Select	c.2205-120C>T		intron	N/A	ENSP00000235329.5
	MFN2	ENST00000675298.1		c.2204+1650C>T		intron	N/A	ENSP00000501839.1
	MFN2	ENST00000675817.1		c.2337-120C>T		intron	N/A	ENSP00000502422.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152124 Hom.: 0 Cov.: 33

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000101 AC: 9 AN: 894692 Hom.: 0 AF XY: 0.00000648 AC XY: 3 AN XY: 463282

African (AFR) AF: 0.0000896 AC: 2 AN: 22332

American (AMR) AF: 0.00 AC: 0 AN: 36780

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22016

East Asian (EAS) AF: 0.00 AC: 0 AN: 35318

South Asian (SAS) AF: 0.00 AC: 0 AN: 70642

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48500

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4704

European-Non Finnish (NFE) AF: 0.0000114 AC: 7 AN: 612794

Other (OTH) AF: 0.00 AC: 0 AN: 41606

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152124 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74312

African (AFR) AF: 0.0000483 AC: 2 AN: 41416

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68008

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 13

Bravo AF: 0.0000189

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.43
DANN	Benign	0.52
PhyloP100		-0.83

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: rs3766741; hg19: chr1-12071433;