rs77262016

Positions:

• chr1-12009741-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_014874.4(MFN2):​c.2204+15T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0606 in 1,614,036 control chromosomes in the GnomAD database, including 3,451 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.076 (541 hom., cov: 33)
  • Exomes 𝑓: 0.059 (2910 hom.)
• Consequence: MFN2 NM_014874.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.0510

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 1-12009741-T-C is Benign according to our data. Variant chr1-12009741-T-C is described in ClinVar as [Benign]. Clinvar id is 138218.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-12009741-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.12 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MFN2	NM_014874.4	c.2204+15T>C		intron_variant		ENST00000235329.10	NP_055689.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MFN2	ENST00000235329.10	c.2204+15T>C		intron_variant		1	NM_014874.4	ENSP00000235329	P1

Frequencies

GnomAD3 genomes AF: 0.0756 AC: 11502 AN: 152190 Hom.: 541 Cov.: 33

Gnomad AFR AF: 0.122

Gnomad AMI AF: 0.0647

Gnomad AMR AF: 0.0544

Gnomad ASJ AF: 0.0893

Gnomad EAS AF: 0.125

Gnomad SAS AF: 0.0754

Gnomad FIN AF: 0.0177

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0570

Gnomad OTH AF: 0.0635

GnomAD3 exomes AF: 0.0623 AC: 15618 AN: 250890 Hom.: 665 AF XY: 0.0625 AC XY: 8481 AN XY: 135672

Gnomad AFR exome AF: 0.129

Gnomad AMR exome AF: 0.0290

Gnomad ASJ exome AF: 0.0895

Gnomad EAS exome AF: 0.129

Gnomad SAS exome AF: 0.0783

Gnomad FIN exome AF: 0.0158

Gnomad NFE exome AF: 0.0547

Gnomad OTH exome AF: 0.0527

GnomAD4 exome AF: 0.0590 AC: 86272 AN: 1461728 Hom.: 2910 Cov.: 32 AF XY: 0.0587 AC XY: 42710 AN XY: 727188

Gnomad4 AFR exome AF: 0.124

Gnomad4 AMR exome AF: 0.0313

Gnomad4 ASJ exome AF: 0.0847

Gnomad4 EAS exome AF: 0.103

Gnomad4 SAS exome AF: 0.0732

Gnomad4 FIN exome AF: 0.0154

Gnomad4 NFE exome AF: 0.0567

Gnomad4 OTH exome AF: 0.0655

GnomAD4 genome AF: 0.0757 AC: 11523 AN: 152308 Hom.: 541 Cov.: 33 AF XY: 0.0745 AC XY: 5549 AN XY: 74474

Gnomad4 AFR AF: 0.122

Gnomad4 AMR AF: 0.0542

Gnomad4 ASJ AF: 0.0893

Gnomad4 EAS AF: 0.125

Gnomad4 SAS AF: 0.0756

Gnomad4 FIN AF: 0.0177

Gnomad4 NFE AF: 0.0570

Gnomad4 OTH AF: 0.0652

Alfa AF: 0.0649 Hom.: 77

Bravo AF: 0.0796

Asia WGS AF: 0.103 AC: 360 AN: 3478

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

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	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Charcot-Marie-Tooth disease Benign:1

Benign, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

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- -

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	-0.86
CADD	Benign	6.0
DANN	Benign	0.45

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

Publications

LitVar

Other links and lift over

dbSNP: rs77262016; hg19: chr1-12069798;