1-11982241-C-T

Variant names:

• chr1-11982241-C-T
• rs76208470
• NM_014874.4:c.-5+127C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_014874.4(MFN2):​c.-5+127C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0487 in 152,240 control chromosomes in the GnomAD database, including 220 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.049 (220 hom., cov: 32)
  • Exomes 𝑓: 0.063 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MFN2 NM_014874.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.547
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• neuropathy, hereditary motor and sensory, type 6A

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• Charcot-Marie-Tooth disease, axonal, autosomal recessive, type 2a2b;

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• axonal hereditary motor and sensory neuropathy

  Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen
• Charcot-Marie-Tooth disease type 2A2

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• hereditary motor and sensory neuropathy type 6

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• multiple symmetric lipomatosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• severe early-onset axonal neuropathy due to MFN2 deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 1-11982241-C-T is Benign according to our data. Variant chr1-11982241-C-T is described in ClinVar as [Benign]. Clinvar id is 1229802.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0758 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MFN2	NM_014874.4	c.-5+127C>T		intron_variant	Intron 2 of 18	ENST00000235329.10	NP_055689.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MFN2	ENST00000235329.10	c.-5+127C>T		intron_variant	Intron 2 of 18	1	NM_014874.4	ENSP00000235329.5

Frequencies

GnomAD3 genomes AF: 0.0487 AC: 7410 AN: 152122 Hom.: 218 Cov.: 32

Gnomad AFR AF: 0.0393

Gnomad AMI AF: 0.0626

Gnomad AMR AF: 0.0424

Gnomad ASJ AF: 0.0778

Gnomad EAS AF: 0.0820

Gnomad SAS AF: 0.0629

Gnomad FIN AF: 0.0123

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0563

Gnomad OTH AF: 0.0484

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0625 AC: 1 AN: 16 Hom.: 0 AF XY: 0.0714 AC XY: 1 AN XY: 14

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.0833 AC: 1 AN: 12

Other (OTH) AF: 0.00 AC: 0 AN: 2

GnomAD4 genome AF: 0.0487 AC: 7418 AN: 152240 Hom.: 220 Cov.: 32 AF XY: 0.0482 AC XY: 3589 AN XY: 74454

African (AFR) AF: 0.0395 AC: 1639 AN: 41546

American (AMR) AF: 0.0423 AC: 647 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0778 AC: 270 AN: 3472

East Asian (EAS) AF: 0.0822 AC: 426 AN: 5180

South Asian (SAS) AF: 0.0636 AC: 306 AN: 4814

European-Finnish (FIN) AF: 0.0123 AC: 131 AN: 10618

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.0563 AC: 3826 AN: 68000

Other (OTH) AF: 0.0474 AC: 100 AN: 2110

Alfa AF: 0.0504 Hom.: 286

Bravo AF: 0.0497

Asia WGS AF: 0.0640 AC: 225 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 29, 2018

GeneDx

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	-0.79
CADD	Benign	2.9
DANN	Benign	0.83
PhyloP100		-0.55
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs76208470; hg19: chr1-12042298;