rs41278632

Variant names:

• chr1-12001541-C-T
• rs41278632
• NM_014874.4:c.957C>T

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PP3 BP6_Very_Strong BS1 BS2

The NM_014874.4(MFN2):​c.957C>T​(p.Gly319Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0102 in 1,614,198 control chromosomes in the GnomAD database, including 126 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0068 (6 hom., cov: 32)
  • Exomes 𝑓: 0.011 (120 hom.)
• Consequence: MFN2 NM_014874.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:10
• Conservation: PhyloP100: 1.33
• Publications: 6 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 -15 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 1-12001541-C-T is Benign according to our data. Variant chr1-12001541-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 138212.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00681 (1038/152336) while in subpopulation NFE AF = 0.0112 (763/68036). AF 95% confidence interval is 0.0106. There are 6 homozygotes in GnomAd4. There are 505 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 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.957C>T	p.Gly319Gly	synonymous	Exon 9 of 19	NP_055689.1	O95140-1
	MFN2	NM_001127660.2		c.957C>T	p.Gly319Gly	synonymous	Exon 8 of 18	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.957C>T	p.Gly319Gly	synonymous	Exon 9 of 19	ENSP00000235329.5	O95140-1
	MFN2	ENST00000675298.1		c.957C>T	p.Gly319Gly	synonymous	Exon 9 of 19	ENSP00000501839.1	A0A6Q8PFJ4
	MFN2	ENST00000675817.1		c.957C>T	p.Gly319Gly	synonymous	Exon 9 of 20	ENSP00000502422.1	A0A6Q8PGV8

Frequencies

GnomAD3 genomes AF: 0.00682 AC: 1038 AN: 152218 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00207

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.00517

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00538

Gnomad FIN AF: 0.00546

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0112

Gnomad OTH AF: 0.00525

GnomAD2 exomes AF: 0.00762 AC: 1916 AN: 251422 AF XY: 0.00799

Gnomad AFR exome AF: 0.00203

Gnomad AMR exome AF: 0.00289

Gnomad ASJ exome AF: 0.00268

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00633

Gnomad NFE exome AF: 0.0122

Gnomad OTH exome AF: 0.00734

GnomAD4 exome AF: 0.0106 AC: 15458 AN: 1461862 Hom.: 120 Cov.: 32 AF XY: 0.0105 AC XY: 7624 AN XY: 727240

African (AFR) AF: 0.00173 AC: 58 AN: 33478

American (AMR) AF: 0.00318 AC: 142 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00184 AC: 48 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00599 AC: 517 AN: 86256

European-Finnish (FIN) AF: 0.00631 AC: 337 AN: 53412

Middle Eastern (MID) AF: 0.00347 AC: 20 AN: 5766

European-Non Finnish (NFE) AF: 0.0125 AC: 13867 AN: 1112002

Other (OTH) AF: 0.00777 AC: 469 AN: 60392

GnomAD4 genome AF: 0.00681 AC: 1038 AN: 152336 Hom.: 6 Cov.: 32 AF XY: 0.00678 AC XY: 505 AN XY: 74500

African (AFR) AF: 0.00207 AC: 86 AN: 41578

American (AMR) AF: 0.00516 AC: 79 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5186

South Asian (SAS) AF: 0.00538 AC: 26 AN: 4830

European-Finnish (FIN) AF: 0.00546 AC: 58 AN: 10618

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0112 AC: 763 AN: 68036

Other (OTH) AF: 0.00520 AC: 11 AN: 2116

Alfa AF: 0.00944 Hom.: 5

Bravo AF: 0.00620

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.0111

EpiControl AF: 0.0108

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	3	not specified (4)
-	-	3	not provided (3)
-	-	2	Charcot-Marie-Tooth disease type 2 (2)
-	-	1	Charcot-Marie-Tooth disease (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	-0.33
CADD	Benign	22
DANN	Benign	0.74
PhyloP100		1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.74		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.74		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs41278632; hg19: chr1-12061598;