1-11980422-T-C

Position:

• chr1-11980422-T-C

Variant summary

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

The ENST00000675298(MFN2):​c.-212T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.502 in 398,038 control chromosomes in the GnomAD database, including 52,435 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.53 (22824 hom., cov: 33)
  • Exomes 𝑓: 0.48 (29611 hom.)
• Consequence: MFN2 ENST00000675298 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.229

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 1-11980422-T-C is Benign according to our data. Variant chr1-11980422-T-C is described in ClinVar as [Benign]. Clinvar id is 292368.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-11980422-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.686 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MFN2	NM_014874.4	c.-212T>C		upstream_gene_variant		ENST00000235329.10	NP_055689.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MFN2	ENST00000235329.10	c.-212T>C		upstream_gene_variant		1	NM_014874.4	ENSP00000235329.5

Frequencies

GnomAD3 genomes AF: 0.533 AC: 80889 AN: 151892 Hom.: 22800 Cov.: 33

Gnomad AFR AF: 0.693

Gnomad AMI AF: 0.246

Gnomad AMR AF: 0.441

Gnomad ASJ AF: 0.324

Gnomad EAS AF: 0.682

Gnomad SAS AF: 0.635

Gnomad FIN AF: 0.563

Gnomad MID AF: 0.392

Gnomad NFE AF: 0.448

Gnomad OTH AF: 0.500

GnomAD4 exome AF: 0.483 AC: 118876 AN: 246028 Hom.: 29611 Cov.: 0 AF XY: 0.479 AC XY: 59770 AN XY: 124706

Gnomad4 AFR exome AF: 0.692

Gnomad4 AMR exome AF: 0.466

Gnomad4 ASJ exome AF: 0.336

Gnomad4 EAS exome AF: 0.614

Gnomad4 SAS exome AF: 0.649

Gnomad4 FIN exome AF: 0.578

Gnomad4 NFE exome AF: 0.448

Gnomad4 OTH exome AF: 0.497

GnomAD4 genome AF: 0.533 AC: 80969 AN: 152010 Hom.: 22824 Cov.: 33 AF XY: 0.537 AC XY: 39897 AN XY: 74312

Gnomad4 AFR AF: 0.693

Gnomad4 AMR AF: 0.441

Gnomad4 ASJ AF: 0.324

Gnomad4 EAS AF: 0.682

Gnomad4 SAS AF: 0.634

Gnomad4 FIN AF: 0.563

Gnomad4 NFE AF: 0.448

Gnomad4 OTH AF: 0.502

Alfa AF: 0.374 Hom.: 1375

Bravo AF: 0.526

Asia WGS AF: 0.674 AC: 2339 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 29, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Charcot-Marie-Tooth disease type 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Hereditary motor and sensory neuropathy with optic atrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

Ehlers-Danlos syndrome, kyphoscoliotic type 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Hereditary motor and sensory neuropathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	7.2
DANN	Benign	0.49
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs2180183; hg19: chr1-12040479;