1-11980267-A-G

Variant names:

• chr1-11980267-A-G
• rs2236054
• ENST00000675298:c.-367A>G

Variant summary

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

The ENST00000444836(MFN2):​c.-222A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.488 in 397,472 control chromosomes in the GnomAD database, including 48,847 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.51 (20267 hom., cov: 32)
  • Exomes 𝑓: 0.48 (28580 hom.)
• Consequence: MFN2 ENST00000444836 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.901

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 1-11980267-A-G is Benign according to our data. Variant chr1-11980267-A-G is described in ClinVar as [Benign]. Clinvar id is 292362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-11980267-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.622 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MFN2	ENST00000675298	c.-367A>G		5_prime_UTR_variant	Exon 1 of 19			ENSP00000501839.1
MFN2	ENST00000675817	c.-367A>G		5_prime_UTR_variant	Exon 1 of 20			ENSP00000502422.1
MFN2	ENST00000444836	c.-222A>G		5_prime_UTR_variant	Exon 1 of 18	2		ENSP00000416338.1

Frequencies

GnomAD3 genomes AF: 0.507 AC: 76910 AN: 151808 Hom.: 20255 Cov.: 32

Gnomad AFR AF: 0.611

Gnomad AMI AF: 0.246

Gnomad AMR AF: 0.430

Gnomad ASJ AF: 0.324

Gnomad EAS AF: 0.640

Gnomad SAS AF: 0.624

Gnomad FIN AF: 0.563

Gnomad MID AF: 0.392

Gnomad NFE AF: 0.447

Gnomad OTH AF: 0.484

GnomAD4 exome AF: 0.476 AC: 116973 AN: 245546 Hom.: 28580 Cov.: 0 AF XY: 0.474 AC XY: 58964 AN XY: 124502

Gnomad4 AFR exome AF: 0.607

Gnomad4 AMR exome AF: 0.457

Gnomad4 ASJ exome AF: 0.335

Gnomad4 EAS exome AF: 0.584

Gnomad4 SAS exome AF: 0.631

Gnomad4 FIN exome AF: 0.577

Gnomad4 NFE exome AF: 0.447

Gnomad4 OTH exome AF: 0.487

GnomAD4 genome AF: 0.507 AC: 76969 AN: 151926 Hom.: 20267 Cov.: 32 AF XY: 0.512 AC XY: 38018 AN XY: 74246

Gnomad4 AFR AF: 0.611

Gnomad4 AMR AF: 0.430

Gnomad4 ASJ AF: 0.324

Gnomad4 EAS AF: 0.640

Gnomad4 SAS AF: 0.623

Gnomad4 FIN AF: 0.563

Gnomad4 NFE AF: 0.447

Gnomad4 OTH AF: 0.483

Alfa AF: 0.433 Hom.: 3962

Bravo AF: 0.496

Asia WGS AF: 0.641 AC: 2229 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 29, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Charcot-Marie-Tooth disease type 2 Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary motor and sensory neuropathy with optic atrophy Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary motor and sensory neuropathy Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

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	-0.86
CADD	Benign	1.5
DANN	Benign	0.52

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: rs2236054; hg19: chr1-12040324;