1-12011376-C-G

Variant names:

• chr1-12011376-C-G
• rs3766741
• NM_014874.4:c.2205-120C>G

Variant summary

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

The NM_014874.4(MFN2):​c.2205-120C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0759 in 1,046,330 control chromosomes in the GnomAD database, including 3,715 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.080 (591 hom., cov: 33)
  • Exomes 𝑓: 0.075 (3124 hom.)
• Consequence: MFN2 NM_014874.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.828
• Publications: 12 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: Labcorp Genetics (formerly Invitae), G2P
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 1-12011376-C-G is Benign according to our data. Variant chr1-12011376-C-G is described in ClinVar as Benign. ClinVar VariationId is 1284248.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.138 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MFN2	NM_014874.4	c.2205-120C>G		intron_variant	Intron 18 of 18	ENST00000235329.10	NP_055689.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MFN2	ENST00000235329.10	c.2205-120C>G		intron_variant	Intron 18 of 18	1	NM_014874.4	ENSP00000235329.5

Frequencies

GnomAD3 genomes AF: 0.0801 AC: 12187 AN: 152108 Hom.: 590 Cov.: 33

Gnomad AFR AF: 0.110

Gnomad AMI AF: 0.0813

Gnomad AMR AF: 0.0410

Gnomad ASJ AF: 0.0352

Gnomad EAS AF: 0.144

Gnomad SAS AF: 0.148

Gnomad FIN AF: 0.0750

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0644

Gnomad OTH AF: 0.0737

GnomAD4 exome AF: 0.0752 AC: 67266 AN: 894104 Hom.: 3124 AF XY: 0.0774 AC XY: 35840 AN XY: 462984

African (AFR) AF: 0.106 AC: 2372 AN: 22324

American (AMR) AF: 0.0345 AC: 1269 AN: 36776

Ashkenazi Jewish (ASJ) AF: 0.0407 AC: 895 AN: 22006

East Asian (EAS) AF: 0.152 AC: 5367 AN: 35288

South Asian (SAS) AF: 0.145 AC: 10244 AN: 70618

European-Finnish (FIN) AF: 0.0761 AC: 3687 AN: 48472

Middle Eastern (MID) AF: 0.0514 AC: 242 AN: 4704

European-Non Finnish (NFE) AF: 0.0652 AC: 39912 AN: 612338

Other (OTH) AF: 0.0788 AC: 3278 AN: 41578

GnomAD4 genome AF: 0.0801 AC: 12193 AN: 152226 Hom.: 591 Cov.: 33 AF XY: 0.0814 AC XY: 6061 AN XY: 74432

African (AFR) AF: 0.110 AC: 4583 AN: 41528

American (AMR) AF: 0.0409 AC: 626 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0352 AC: 122 AN: 3470

East Asian (EAS) AF: 0.144 AC: 744 AN: 5178

South Asian (SAS) AF: 0.147 AC: 711 AN: 4828

European-Finnish (FIN) AF: 0.0750 AC: 796 AN: 10608

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0644 AC: 4376 AN: 67998

Other (OTH) AF: 0.0734 AC: 155 AN: 2112

Alfa AF: 0.0277 Hom.: 13

Bravo AF: 0.0754

Asia WGS AF: 0.151 AC: 524 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 23, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.20
DANN	Benign	0.45
PhyloP100		-0.83
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: rs3766741; hg19: chr1-12071433; COSMIC: COSV52422123;