ENST00000675298:c.-367A>G

Variant names:

• chr1-11980267-A-G
• rs2236054
• ENST00000675298.1:c.-367A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000675298.1(MFN2):​c.-367A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.488 in 397,472 control chromosomes in the GnomAD database, including 48,847 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.51 (20267 hom., cov: 32)
  • Exomes 𝑓: 0.48 (28580 hom.)
• Consequence: MFN2 ENST00000675298.1 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.901
• Publications: 8 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

ENSG00000287384 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 1-11980267-A-G is Benign according to our data. Variant chr1-11980267-A-G is described in ClinVar as Benign. ClinVar VariationId is 292362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.622 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000675298.1. 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.-367A>G		upstream_gene	N/A	NP_055689.1	O95140-1
	MFN2	NM_001127660.2		c.-222A>G		upstream_gene	N/A	NP_001121132.1	O95140-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MFN2	ENST00000675298.1		c.-367A>G		5_prime_UTR	Exon 1 of 19	ENSP00000501839.1	A0A6Q8PFJ4
	MFN2	ENST00000675817.1		c.-367A>G		5_prime_UTR	Exon 1 of 20	ENSP00000502422.1	A0A6Q8PGV8
	MFN2	ENST00000898885.1		c.-367A>G		5_prime_UTR	Exon 1 of 20	ENSP00000568944.1

Frequencies

GnomAD3 genomes AF: 0.507 AC: 76910 AN: 151808 Hom.: 20255 Cov.: 32

Gnomad AFR AF: 0.611

Gnomad AMI AF: 0.246

Gnomad AMR AF: 0.430

Gnomad ASJ AF: 0.324

Gnomad EAS AF: 0.640

Gnomad SAS AF: 0.624

Gnomad FIN AF: 0.563

Gnomad MID AF: 0.392

Gnomad NFE AF: 0.447

Gnomad OTH AF: 0.484

GnomAD4 exome AF: 0.476 AC: 116973 AN: 245546 Hom.: 28580 Cov.: 0 AF XY: 0.474 AC XY: 58964 AN XY: 124502

African (AFR) AF: 0.607 AC: 4336 AN: 7138

American (AMR) AF: 0.457 AC: 3378 AN: 7392

Ashkenazi Jewish (ASJ) AF: 0.335 AC: 3081 AN: 9202

East Asian (EAS) AF: 0.584 AC: 13358 AN: 22862

South Asian (SAS) AF: 0.631 AC: 1909 AN: 3026

European-Finnish (FIN) AF: 0.577 AC: 12017 AN: 20812

Middle Eastern (MID) AF: 0.413 AC: 534 AN: 1292

European-Non Finnish (NFE) AF: 0.447 AC: 70426 AN: 157514

Other (OTH) AF: 0.487 AC: 7934 AN: 16308

GnomAD4 genome AF: 0.507 AC: 76969 AN: 151926 Hom.: 20267 Cov.: 32 AF XY: 0.512 AC XY: 38018 AN XY: 74246

African (AFR) AF: 0.611 AC: 25306 AN: 41450

American (AMR) AF: 0.430 AC: 6567 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.324 AC: 1122 AN: 3468

East Asian (EAS) AF: 0.640 AC: 3293 AN: 5144

South Asian (SAS) AF: 0.623 AC: 3005 AN: 4820

European-Finnish (FIN) AF: 0.563 AC: 5937 AN: 10542

Middle Eastern (MID) AF: 0.388 AC: 114 AN: 294

European-Non Finnish (NFE) AF: 0.447 AC: 30383 AN: 67904

Other (OTH) AF: 0.483 AC: 1019 AN: 2110

Alfa AF: 0.444 Hom.: 5286

Bravo AF: 0.496

Asia WGS AF: 0.641 AC: 2229 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Charcot-Marie-Tooth disease type 2 (1)
-	-	1	Ehlers-Danlos syndrome, kyphoscoliotic type 1 (1)
-	-	1	Hereditary motor and sensory neuropathy (1)
-	-	1	Hereditary motor and sensory neuropathy with optic atrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.5
DANN	Benign	0.52
PhyloP100		-0.90
PromoterAI		-0.0087	Neutral
Mutation Taster		=298/2	polymorphism (auto)

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: rs2236054; hg19: chr1-12040324;