1-11980385-T-A

Variant names:

• chr1-11980385-T-A
• rs2180182
• ENST00000675298:c.-249T>A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000444836(MFN2):​c.-104T>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00672 in 398,316 control chromosomes in the GnomAD database, including 67 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (53 hom., cov: 33)
  • Exomes 𝑓: 0.0020 (14 hom.)
• Consequence: MFN2 ENST00000444836 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.431

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=-0.81).
• BP6: Variant 1-11980385-T-A is Benign according to our data. Variant chr1-11980385-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 292366.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0144 (2192/152230) while in subpopulation AFR AF= 0.0493 (2047/41532). AF 95% confidence interval is 0.0475. There are 53 homozygotes in gnomad4. There are 1002 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 53 SD gene

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.-249T>A		5_prime_UTR_variant	Exon 1 of 19			ENSP00000501839.1
MFN2	ENST00000675817	c.-249T>A		5_prime_UTR_variant	Exon 1 of 20			ENSP00000502422.1
MFN2	ENST00000444836	c.-104T>A		5_prime_UTR_variant	Exon 1 of 18	2		ENSP00000416338.1

Frequencies

GnomAD3 genomes AF: 0.0144 AC: 2186 AN: 152112 Hom.: 53 Cov.: 33

Gnomad AFR AF: 0.0493

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00753

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00908

GnomAD4 exome AF: 0.00196 AC: 483 AN: 246086 Hom.: 14 Cov.: 0 AF XY: 0.00151 AC XY: 188 AN XY: 124756

Gnomad4 AFR exome AF: 0.0487

Gnomad4 AMR exome AF: 0.00592

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000823

Gnomad4 OTH exome AF: 0.00471

GnomAD4 genome AF: 0.0144 AC: 2192 AN: 152230 Hom.: 53 Cov.: 33 AF XY: 0.0135 AC XY: 1002 AN XY: 74444

Gnomad4 AFR AF: 0.0493

Gnomad4 AMR AF: 0.00745

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00899

Alfa AF: 0.00985 Hom.: 3

Bravo AF: 0.0169

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Charcot-Marie-Tooth disease type 2 Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary motor and sensory neuropathy with optic atrophy Benign:1

Jan 13, 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. -

not provided Benign:1

Dec 21, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

See Variant Classification Assertion Criteria. -

Hereditary motor and sensory neuropathy Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely 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	-0.81
CADD	Benign	6.1
DANN	Benign	0.75

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: rs2180182; hg19: chr1-12040442;