Genetic Variant MFN2:c.-149-38dupT (chr1-11981920-G-GT) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1BS2

The NM_014874.4(MFN2):c.-149-38dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. There are indicators that this mutation may affect the branch point..

Frequency

Genomes: 𝑓 0.011 ( 23 hom., cov: 0)

Failed GnomAD Quality Control

Consequence

MFN2
NM_014874.4 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.194

Publications

0 publications found

Variant links:

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

MFN2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0114 (1575/137930) while in subpopulation NFE AF = 0.0184 (1200/65234). AF 95% confidence interval is 0.0175. There are 23 homozygotes in GnomAd4. There are 725 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 23 AD,AR,SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MFN2	NM_014874.4 link	c.-149-38dupT		intron_variant	Intron 1 of 18	ENST00000235329.10	NP_055689.1	O95140-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MFN2	ENST00000235329.10 link	c.-149-38dupT		intron_variant	Intron 1 of 18	1	NM_014874.4	ENSP00000235329.5		O95140-1

Frequencies

GnomAD3 genomes

AF:

0.0114

AC:

1575

AN:

137924

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00321

Gnomad AMI

AF:

0.00905

Gnomad AMR

AF:

0.0120

Gnomad ASJ

AF:

0.00326

Gnomad EAS

AF:

0.000847

Gnomad SAS

AF:

0.00494

Gnomad FIN

AF:

0.00401

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0184

Gnomad OTH

AF:

0.00954

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AC:

AN:

Hom.:

Cov.:

AC XY:

AN XY:

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AC:

AN:

Other (OTH)

AC:

AN:

GnomAD4 genome

AF:

0.0114

AC:

1575

AN:

137930

Hom.:

Cov.:

AF XY:

0.0109

AC XY:

725

AN XY:

66216

show subpopulations

African (AFR)

AF:

0.00320

AC:

114

AN:

35610

American (AMR)

AF:

0.0120

AC:

168

AN:

14056

Ashkenazi Jewish (ASJ)

AF:

0.00326

AC:

AN:

3374

East Asian (EAS)

AF:

0.000850

AC:

AN:

4708

South Asian (SAS)

AF:

0.00496

AC:

AN:

4434

European-Finnish (FIN)

AF:

0.00401

AC:

AN:

7472

Middle Eastern (MID)

AF:

0.00

AC:

AN:

262

European-Non Finnish (NFE)

AF:

0.0184

AC:

1200

AN:

65234

Other (OTH)

AF:

0.00949

AC:

AN:

1896

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

136

204

272

340

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00342

Hom.:

244

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.19

BranchPoint Hunter

3.0

Mutation Taster

=100/0

polymorphism

(source)

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

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1-11981920-GTTTT-GTTTTT

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over