NM_014874.4:c.1160+45A>G

Variant names:

• chr1-12002148-A-G
• rs2236057
• NM_014874.4:c.1160+45A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_014874.4(MFN2):​c.1160+45A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.661 in 1,613,350 control chromosomes in the GnomAD database, including 353,990 homozygotes. 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 0.65 (32398 hom., cov: 34)
  • Exomes 𝑓: 0.66 (321592 hom.)
• Consequence: MFN2 NM_014874.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.38
• Publications: 25 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.689 is higher than 0.05.

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.1160+45A>G		intron	N/A	NP_055689.1	O95140-1
	MFN2	NM_001127660.2		c.1160+45A>G		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.1160+45A>G		intron	N/A	ENSP00000235329.5	O95140-1
	MFN2	ENST00000675298.1		c.1160+45A>G		intron	N/A	ENSP00000501839.1	A0A6Q8PFJ4
	MFN2	ENST00000675817.1		c.1160+45A>G		intron	N/A	ENSP00000502422.1	A0A6Q8PGV8

Frequencies

GnomAD3 genomes AF: 0.649 AC: 98694 AN: 152098 Hom.: 32381 Cov.: 34

Gnomad AFR AF: 0.647

Gnomad AMI AF: 0.489

Gnomad AMR AF: 0.553

Gnomad ASJ AF: 0.503

Gnomad EAS AF: 0.681

Gnomad SAS AF: 0.708

Gnomad FIN AF: 0.726

Gnomad MID AF: 0.620

Gnomad NFE AF: 0.663

Gnomad OTH AF: 0.632

GnomAD2 exomes AF: 0.652 AC: 163153 AN: 250174 AF XY: 0.656

Gnomad AFR exome AF: 0.648

Gnomad AMR exome AF: 0.532

Gnomad ASJ exome AF: 0.527

Gnomad EAS exome AF: 0.677

Gnomad FIN exome AF: 0.731

Gnomad NFE exome AF: 0.668

Gnomad OTH exome AF: 0.649

GnomAD4 exome AF: 0.662 AC: 967010 AN: 1461134 Hom.: 321592 Cov.: 52 AF XY: 0.663 AC XY: 481536 AN XY: 726834

African (AFR) AF: 0.645 AC: 21602 AN: 33472

American (AMR) AF: 0.539 AC: 24095 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.521 AC: 13610 AN: 26114

East Asian (EAS) AF: 0.640 AC: 25399 AN: 39684

South Asian (SAS) AF: 0.704 AC: 60596 AN: 86060

European-Finnish (FIN) AF: 0.730 AC: 38962 AN: 53354

Middle Eastern (MID) AF: 0.667 AC: 3844 AN: 5764

European-Non Finnish (NFE) AF: 0.665 AC: 738789 AN: 1111648

Other (OTH) AF: 0.665 AC: 40113 AN: 60360

GnomAD4 genome AF: 0.649 AC: 98766 AN: 152216 Hom.: 32398 Cov.: 34 AF XY: 0.649 AC XY: 48314 AN XY: 74420

African (AFR) AF: 0.647 AC: 26873 AN: 41528

American (AMR) AF: 0.553 AC: 8459 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.503 AC: 1745 AN: 3472

East Asian (EAS) AF: 0.682 AC: 3527 AN: 5174

South Asian (SAS) AF: 0.708 AC: 3422 AN: 4830

European-Finnish (FIN) AF: 0.726 AC: 7699 AN: 10598

Middle Eastern (MID) AF: 0.602 AC: 177 AN: 294

European-Non Finnish (NFE) AF: 0.663 AC: 45080 AN: 67996

Other (OTH) AF: 0.633 AC: 1340 AN: 2116

Alfa AF: 0.654 Hom.: 127984

Bravo AF: 0.633

Asia WGS AF: 0.704 AC: 2446 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.76
DANN	Benign	0.41
PhyloP100		-2.4
Mutation Taster		=100/0	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: rs2236057; hg19: chr1-12062205; COSMIC: COSV52420984;