rs2295281

Variant names:

• chr1-11999355-C-T
• rs2295281
• NM_014874.4:c.816+260C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-11999355-C-T
• chr1-11999355-C-A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_014874.4(MFN2):​c.816+260C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.46 in 151,936 control chromosomes in the GnomAD database, including 17,069 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.46 (17069 hom., cov: 31)
• Consequence: MFN2 NM_014874.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0300
• Publications: 31 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 1-11999355-C-T is Benign according to our data. Variant chr1-11999355-C-T is described in ClinVar as Benign. ClinVar VariationId is 684255.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.526 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.816+260C>T		intron	N/A	NP_055689.1	O95140-1
	MFN2	NM_001127660.2		c.816+260C>T		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.816+260C>T		intron	N/A	ENSP00000235329.5	O95140-1
	MFN2	ENST00000675298.1		c.816+260C>T		intron	N/A	ENSP00000501839.1	A0A6Q8PFJ4
	MFN2	ENST00000675817.1		c.816+260C>T		intron	N/A	ENSP00000502422.1	A0A6Q8PGV8

Frequencies

GnomAD3 genomes AF: 0.460 AC: 69870 AN: 151818 Hom.: 17069 Cov.: 31

Gnomad AFR AF: 0.320

Gnomad AMI AF: 0.335

Gnomad AMR AF: 0.447

Gnomad ASJ AF: 0.375

Gnomad EAS AF: 0.409

Gnomad SAS AF: 0.466

Gnomad FIN AF: 0.632

Gnomad MID AF: 0.500

Gnomad NFE AF: 0.531

Gnomad OTH AF: 0.466

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.460 AC: 69901 AN: 151936 Hom.: 17069 Cov.: 31 AF XY: 0.462 AC XY: 34324 AN XY: 74270

African (AFR) AF: 0.320 AC: 13242 AN: 41406

American (AMR) AF: 0.447 AC: 6829 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.375 AC: 1302 AN: 3472

East Asian (EAS) AF: 0.410 AC: 2114 AN: 5160

South Asian (SAS) AF: 0.467 AC: 2249 AN: 4818

European-Finnish (FIN) AF: 0.632 AC: 6663 AN: 10546

Middle Eastern (MID) AF: 0.490 AC: 144 AN: 294

European-Non Finnish (NFE) AF: 0.531 AC: 36071 AN: 67948

Other (OTH) AF: 0.467 AC: 983 AN: 2106

Alfa AF: 0.508 Hom.: 84701

Bravo AF: 0.442

Asia WGS AF: 0.435 AC: 1513 AN: 3478

ClinVar

ClinVar submissions

Significance: 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
BayesDel_noAF	Benign	-0.80
CADD	Benign	5.8
DANN	Benign	0.74
PhyloP100		0.030
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: rs2295281; hg19: chr1-12059412;