1-12006987-T-G

Position:

• chr1-12006987-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_014874.4(MFN2):​c.1873-66T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.588 in 1,593,006 control chromosomes in the GnomAD database, including 278,818 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.54 (23205 hom., cov: 32)
  • Exomes 𝑓: 0.59 (255613 hom.)
• Consequence: MFN2 NM_014874.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.156

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=-0.88).
• BP6: Variant 1-12006987-T-G is Benign according to our data. Variant chr1-12006987-T-G is described in ClinVar as [Benign]. Clinvar id is 676150.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-12006987-T-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.602 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MFN2	NM_014874.4	c.1873-66T>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.1873-66T>G		intron_variant		1	NM_014874.4	ENSP00000235329	P1

Frequencies

GnomAD3 genomes AF: 0.545 AC: 82744 AN: 151952 Hom.: 23202 Cov.: 32

Gnomad AFR AF: 0.442

Gnomad AMI AF: 0.411

Gnomad AMR AF: 0.489

Gnomad ASJ AF: 0.409

Gnomad EAS AF: 0.555

Gnomad SAS AF: 0.621

Gnomad FIN AF: 0.707

Gnomad MID AF: 0.532

Gnomad NFE AF: 0.597

Gnomad OTH AF: 0.548

GnomAD4 exome AF: 0.593 AC: 854223 AN: 1440936 Hom.: 255613 AF XY: 0.594 AC XY: 426491 AN XY: 717982

Gnomad4 AFR exome AF: 0.437

Gnomad4 AMR exome AF: 0.499

Gnomad4 ASJ exome AF: 0.433

Gnomad4 EAS exome AF: 0.535

Gnomad4 SAS exome AF: 0.619

Gnomad4 FIN exome AF: 0.711

Gnomad4 NFE exome AF: 0.600

Gnomad4 OTH exome AF: 0.585

GnomAD4 genome AF: 0.544 AC: 82786 AN: 152070 Hom.: 23205 Cov.: 32 AF XY: 0.547 AC XY: 40638 AN XY: 74340

Gnomad4 AFR AF: 0.442

Gnomad4 AMR AF: 0.489

Gnomad4 ASJ AF: 0.409

Gnomad4 EAS AF: 0.556

Gnomad4 SAS AF: 0.621

Gnomad4 FIN AF: 0.707

Gnomad4 NFE AF: 0.597

Gnomad4 OTH AF: 0.548

Alfa AF: 0.586 Hom.: 11380

Bravo AF: 0.522

Asia WGS AF: 0.591 AC: 2054 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.79
DANN	Benign	0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs7550536; hg19: chr1-12067044; COSMIC: COSV52424175;