chr1-12002044-G-C

Position:

chr1-12002044-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PM5PP2

The ENST00000235329.10(MFN2):c.1101G>C(p.Gln367His) variant causes a missense change. The variant allele was found at a frequency of 0.0000576 in 1,614,150 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q367P) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.00024 ( 1 hom., cov: 33)

Exomes 𝑓: 0.000039 ( 0 hom. )

Consequence

MFN2
ENST00000235329.10 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 5.61

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in ENST00000235329.10

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-12002043-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 2202705.Status of the report is criteria_provided_single_submitter, 1 stars.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), MFN2. . Gene score misZ 1.6575 (greater than the threshold 3.09). Trascript score misZ 3.2174 (greater than threshold 3.09). GenCC has associacion of gene with Charcot-Marie-Tooth disease type 2A2, axonal hereditary motor and sensory neuropathy, hereditary motor and sensory neuropathy type 6, Charcot-Marie-Tooth disease, axonal, autosomal recessive, type 2a2b;, multiple symmetric lipomatosis, severe early-onset axonal neuropathy due to MFN2 deficiency.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MFN2	NM_014874.4 linkuse as main transcript	c.1101G>C	p.Gln367His	missense_variant	11/19	ENST00000235329.10	NP_055689.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MFN2	ENST00000235329.10 linkuse as main transcript	c.1101G>C	p.Gln367His	missense_variant	11/19	1	NM_014874.4	ENSP00000235329	P1	O95140-1

Frequencies

GnomAD3 genomes

AF:

0.000236

AC:

AN:

152258

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00235

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000103

AC:

AN:

251496

Hom.:

AF XY:

0.0000736

AC XY:

AN XY:

135922

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000694

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000390

AC:

AN:

1461892

Hom.:

Cov.:

AF XY:

0.0000234

AC XY:

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000514

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:

0.0000297

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.000236

AC:

AN:

152258

Hom.:

Cov.:

AF XY:

0.000403

AC XY:

AN XY:

74390

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00235

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.000242

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Apr 05, 2017

- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 13, 2021

The p.Q367H variant (also known as c.1101G>C), located in coding exon 9 of the MFN2 gene, results from a G to C substitution at nucleotide position 1101. The glutamine at codon 367 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the supporting evidence, this variant is unlikely to be causative of Charcot-Marie-Tooth disease, axonal, type 2A2A and/or hereditary motor and sensory neuropathy VIA; however, its contribution to the development of Charcot-Marie-Tooth disease, axonal, type 2A2B is uncertain. -

Charcot-Marie-Tooth disease, axonal, autosomal recessive, type 2a2b;

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

3billion

Jul 30, 2024

The variant is observed at an extremely low frequency in the gnomAD v4.0.0 dataset (total allele frequency: 0.006%). Damaging effect on gene or gene product predicted by in silico programs is uncertain [REVEL: 0.53 (damaging >=0.6, benign <0.4), 3Cnet: 0.44 (damaging >=0.6, benign <0.15)]. The same nucleotide change resulting in the same amino acid change has been previously reported to be associated with MFN2-related disorder (ClinVar ID: VCV000439898 / PMID: 33415332 / 3billion dataset). A different missense change at the same codon (p.Gln367Pro) has been reported to be associated with MFN2 related disorder (ClinVar ID: VCV002202705 / PMID: 26801520). Therefore, this variant is classified as uncertain significance according to the recommendation of ACMG/AMP guideline. -

Charcot-Marie-Tooth disease type 2

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 09, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.023

BayesDel_noAF

Uncertain

0.10

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.61

D;D

Eigen

Benign

-0.15

Eigen_PC

Benign

0.019

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.85

D;.

M_CAP

Uncertain

0.18

MetaRNN

Uncertain

0.54

D;D

MetaSVM

Uncertain

0.32

MutationAssessor

Uncertain

2.4

M;M

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-2.2

N;N

REVEL

Uncertain

0.53

Sift

Benign

0.13

T;T

Sift4G

Benign

0.15

T;T

Polyphen

0.0070

B;B

Vest4

0.76

MutPred

0.41

Loss of helix (P = 0.0167);Loss of helix (P = 0.0167);

MVP

0.94

MPC

0.69

ClinPred

0.10

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.46

gMVP

0.73

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over