rs2236057

Positions:

• chr1-12002148-A-G
• chr1-12002148-A-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_014874.4(MFN2):​c.1160+45A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.661 in 1,613,350 control chromosomes in the GnomAD database, including 353,990 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in Lovd as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.65 (32398 hom., cov: 34)
  • Exomes 𝑓: 0.66 (321592 hom.)
• Consequence: MFN2 NM_014874.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.38

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 1-12002148-A-G is Benign according to our data. Variant chr1-12002148-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.689 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MFN2	NM_014874.4	c.1160+45A>G		intron_variant		ENST00000235329.10	NP_055689.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MFN2	ENST00000235329.10	c.1160+45A>G		intron_variant		1	NM_014874.4	ENSP00000235329	P1

Frequencies

GnomAD3 genomes AF: 0.649 AC: 98694 AN: 152098 Hom.: 32381 Cov.: 34

Gnomad AFR AF: 0.647

Gnomad AMI AF: 0.489

Gnomad AMR AF: 0.553

Gnomad ASJ AF: 0.503

Gnomad EAS AF: 0.681

Gnomad SAS AF: 0.708

Gnomad FIN AF: 0.726

Gnomad MID AF: 0.620

Gnomad NFE AF: 0.663

Gnomad OTH AF: 0.632

GnomAD3 exomes AF: 0.652 AC: 163153 AN: 250174 Hom.: 53888 AF XY: 0.656 AC XY: 88831 AN XY: 135322

Gnomad AFR exome AF: 0.648

Gnomad AMR exome AF: 0.532

Gnomad ASJ exome AF: 0.527

Gnomad EAS exome AF: 0.677

Gnomad SAS exome AF: 0.703

Gnomad FIN exome AF: 0.731

Gnomad NFE exome AF: 0.668

Gnomad OTH exome AF: 0.649

GnomAD4 exome AF: 0.662 AC: 967010 AN: 1461134 Hom.: 321592 Cov.: 52 AF XY: 0.663 AC XY: 481536 AN XY: 726834

Gnomad4 AFR exome AF: 0.645

Gnomad4 AMR exome AF: 0.539

Gnomad4 ASJ exome AF: 0.521

Gnomad4 EAS exome AF: 0.640

Gnomad4 SAS exome AF: 0.704

Gnomad4 FIN exome AF: 0.730

Gnomad4 NFE exome AF: 0.665

Gnomad4 OTH exome AF: 0.665

GnomAD4 genome AF: 0.649 AC: 98766 AN: 152216 Hom.: 32398 Cov.: 34 AF XY: 0.649 AC XY: 48314 AN XY: 74420

Gnomad4 AFR AF: 0.647

Gnomad4 AMR AF: 0.553

Gnomad4 ASJ AF: 0.503

Gnomad4 EAS AF: 0.682

Gnomad4 SAS AF: 0.708

Gnomad4 FIN AF: 0.726

Gnomad4 NFE AF: 0.663

Gnomad4 OTH AF: 0.633

Alfa AF: 0.650 Hom.: 55990

Bravo AF: 0.633

Asia WGS AF: 0.704 AC: 2446 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.76
DANN	Benign	0.41

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: rs2236057; hg19: chr1-12062205; COSMIC: COSV52420984;