rs1042837

Positions:

• chr1-12005784-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_014874.4(MFN2):​c.1569C>T​(p.Ser523Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0552 in 1,614,182 control chromosomes in the GnomAD database, including 2,840 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.047 (234 hom., cov: 33)
  • Exomes 𝑓: 0.056 (2606 hom.)
• Consequence: MFN2 NM_014874.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.654

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 1-12005784-C-T is Benign according to our data. Variant chr1-12005784-C-T is described in ClinVar as [Benign]. Clinvar id is 138215.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-12005784-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.654 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.118 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MFN2	NM_014874.4	c.1569C>T	p.Ser523Ser	synonymous_variant	15/19	ENST00000235329.10	NP_055689.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MFN2	ENST00000235329.10	c.1569C>T	p.Ser523Ser	synonymous_variant	15/19	1	NM_014874.4	ENSP00000235329.5

Frequencies

GnomAD3 genomes AF: 0.0468 AC: 7128 AN: 152202 Hom.: 233 Cov.: 33

Gnomad AFR AF: 0.0234

Gnomad AMI AF: 0.0647

Gnomad AMR AF: 0.0419

Gnomad ASJ AF: 0.0815

Gnomad EAS AF: 0.126

Gnomad SAS AF: 0.0751

Gnomad FIN AF: 0.0177

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0567

Gnomad OTH AF: 0.0460

GnomAD3 exomes AF: 0.0545 AC: 13696 AN: 251496 Hom.: 500 AF XY: 0.0570 AC XY: 7750 AN XY: 135922

Gnomad AFR exome AF: 0.0228

Gnomad AMR exome AF: 0.0236

Gnomad ASJ exome AF: 0.0834

Gnomad EAS exome AF: 0.132

Gnomad SAS exome AF: 0.0782

Gnomad FIN exome AF: 0.0159

Gnomad NFE exome AF: 0.0545

Gnomad OTH exome AF: 0.0492

GnomAD4 exome AF: 0.0561 AC: 82027 AN: 1461862 Hom.: 2606 Cov.: 32 AF XY: 0.0563 AC XY: 40951 AN XY: 727236

Gnomad4 AFR exome AF: 0.0231

Gnomad4 AMR exome AF: 0.0255

Gnomad4 ASJ exome AF: 0.0795

Gnomad4 EAS exome AF: 0.105

Gnomad4 SAS exome AF: 0.0733

Gnomad4 FIN exome AF: 0.0155

Gnomad4 NFE exome AF: 0.0566

Gnomad4 OTH exome AF: 0.0589

GnomAD4 genome AF: 0.0468 AC: 7133 AN: 152320 Hom.: 234 Cov.: 33 AF XY: 0.0470 AC XY: 3504 AN XY: 74482

Gnomad4 AFR AF: 0.0235

Gnomad4 AMR AF: 0.0418

Gnomad4 ASJ AF: 0.0815

Gnomad4 EAS AF: 0.126

Gnomad4 SAS AF: 0.0756

Gnomad4 FIN AF: 0.0177

Gnomad4 NFE AF: 0.0567

Gnomad4 OTH AF: 0.0450

Alfa AF: 0.0502 Hom.: 102

Bravo AF: 0.0469

Asia WGS AF: 0.0910 AC: 317 AN: 3478

EpiCase AF: 0.0567

EpiControl AF: 0.0609

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 24, 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. -

Charcot-Marie-Tooth disease type 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
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. -

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. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	10
DANN	Benign	0.83
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1042837; hg19: chr1-12065841; COSMIC: COSV52422680;