rs41278632

chr1-12001541-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 1P and 12B. PP3 BP6_Very_Strong BS2

The NM_014874.4(MFN2):c.957C>T(p.Gly319=) 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:9
• Conservation: PhyloP100: 1.33

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]

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• PP3: Splicing scoreres supports a deletorius 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 [Likely_benign]. Clinvar id is 138212.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-12001541-C-T is described in Lovd as [Benign].
• BS2: High Homozygotes in GnomAd at 6 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MFN2	NM_014874.4	c.957C>T	p.Gly319=	synonymous_variant	9/19	ENST00000235329.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MFN2	ENST00000235329.10	c.957C>T	p.Gly319=	synonymous_variant	9/19	1	NM_014874.4	P1

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

GnomAD3 exomes AF: 0.00762 AC: 1916 AN: 251422 Hom.: 12 AF XY: 0.00799 AC XY: 1086 AN XY: 135902

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 SAS exome AF: 0.00594

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

Gnomad4 AFR exome AF: 0.00173

Gnomad4 AMR exome AF: 0.00318

Gnomad4 ASJ exome AF: 0.00184

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00599

Gnomad4 FIN exome AF: 0.00631

Gnomad4 NFE exome AF: 0.0125

Gnomad4 OTH exome AF: 0.00777

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

Gnomad4 AFR AF: 0.00207

Gnomad4 AMR AF: 0.00516

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00538

Gnomad4 FIN AF: 0.00546

Gnomad4 NFE AF: 0.0112

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00921 Hom.: 4

Bravo AF: 0.00620

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.0111

EpiControl AF: 0.0108

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1 Benign:3

Uncertain significance, no assertion criteria provided	literature only	Inherited Neuropathy Consortium	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 26, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 17, 2019	- -

Charcot-Marie-Tooth disease type 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	MFN2: PP3, BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 09, 2023	- -

Charcot-Marie-Tooth disease Benign:1

Benign, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

-

- -

Hereditary motor and sensory neuropathy with optic atrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
Cadd	Benign	22
Dann	Benign	0.74
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs41278632; hg19: chr1-12061598;