NM_014874.4:c.-149-46_-149-45insGTTTTTTTTT

Variant names:

• chr1-11981920-G-GTTTTGTTTTT
• rs763918741
• NM_014874.4:c.-149-46_-149-45insGTTTTTTTTT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_014874.4(MFN2):​c.-149-46_-149-45insGTTTTTTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★). There are indicators that this mutation may affect the branch point..

• Frequency: Genomes: 𝑓 0.0031 (4 hom., cov: 0)
• Consequence: MFN2 NM_014874.4 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.194
• Publications: 0 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: Benign. The variant received -10 ACMG points.

• BP6: Variant 1-11981920-G-GTTTTGTTTTT is Benign according to our data. Variant chr1-11981920-G-GTTTTGTTTTT is described in ClinVar as Likely_benign. ClinVar VariationId is 1691171.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00307 (423/138008) while in subpopulation AFR AF = 0.0112 (398/35610). AF 95% confidence interval is 0.0103. There are 4 homozygotes in GnomAd4. There are 198 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR,AD,SD gene

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.-149-46_-149-45insGTTTTTTTTT		intron	N/A	NP_055689.1	O95140-1
	MFN2	NM_001127660.2		c.-5+1440_-5+1441insGTTTTTTTTT		intron	N/A	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.-149-46_-149-45insGTTTTTTTTT		intron	N/A	ENSP00000235329.5	O95140-1
	MFN2	ENST00000675231.1		c.-263_-262insGTTTTTTTTT		5_prime_UTR	Exon 2 of 20	ENSP00000502404.1	O95140-1
	MFN2	ENST00000675781.1		c.-195_-194insGTTTTTTTTT		5_prime_UTR	Exon 2 of 4	ENSP00000501947.1	A0A6Q8PFT5

Frequencies

GnomAD3 genomes AF: 0.00307 AC: 423 AN: 138002 Hom.: 4 Cov.: 0

Gnomad AFR AF: 0.0112

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000926

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: 0.000123

Gnomad OTH AF: 0.00212

GnomAD4 exome Cov.: 0

GnomAD4 genome AF: 0.00307 AC: 423 AN: 138008 Hom.: 4 Cov.: 0 AF XY: 0.00299 AC XY: 198 AN XY: 66270

African (AFR) AF: 0.0112 AC: 398 AN: 35610

American (AMR) AF: 0.000925 AC: 13 AN: 14058

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3376

East Asian (EAS) AF: 0.00 AC: 0 AN: 4708

South Asian (SAS) AF: 0.00 AC: 0 AN: 4436

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7484

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 262

European-Non Finnish (NFE) AF: 0.000123 AC: 8 AN: 65294

Other (OTH) AF: 0.00211 AC: 4 AN: 1896

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.19
BranchPoint Hunter		3.0
Mutation Taster		=100/0	polymorphism

Splicing

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.

Other links and lift over

dbSNP: rs763918741; hg19: chr1-12041977;