1-12006987-T-G

Variant names:

• chr1-12006987-T-G
• rs7550536
• NM_014874.4:c.1873-66T>G

Variant summary

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

The ENST00000235329.10(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 ENST00000235329.10 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.156
• Publications: 21 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=-0.88).
• BP6: Variant 1-12006987-T-G is Benign according to our data. Variant chr1-12006987-T-G is described in ClinVar as Benign. ClinVar VariationId is 676150.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.602 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000235329.10. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MFN2	NM_014874.4	MANE Select	c.1873-66T>G		intron	N/A	NP_055689.1
	MFN2	NM_001127660.2		c.1873-66T>G		intron	N/A	NP_001121132.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MFN2	ENST00000235329.10	TSL:1 MANE Select	c.1873-66T>G		intron	N/A	ENSP00000235329.5
	MFN2	ENST00000676295.1		n.220T>G		non_coding_transcript_exon	Exon 1 of 3
	MFN2	ENST00000675298.1		c.1873-66T>G		intron	N/A	ENSP00000501839.1

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

African (AFR) AF: 0.437 AC: 14415 AN: 32978

American (AMR) AF: 0.499 AC: 22289 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.433 AC: 11270 AN: 26018

East Asian (EAS) AF: 0.535 AC: 21188 AN: 39612

South Asian (SAS) AF: 0.619 AC: 53012 AN: 85620

European-Finnish (FIN) AF: 0.711 AC: 37649 AN: 52950

Middle Eastern (MID) AF: 0.565 AC: 2362 AN: 4178

European-Non Finnish (NFE) AF: 0.600 AC: 657164 AN: 1095260

Other (OTH) AF: 0.585 AC: 34874 AN: 59630

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

African (AFR) AF: 0.442 AC: 18317 AN: 41478

American (AMR) AF: 0.489 AC: 7472 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.409 AC: 1420 AN: 3468

East Asian (EAS) AF: 0.556 AC: 2870 AN: 5166

South Asian (SAS) AF: 0.621 AC: 2989 AN: 4814

European-Finnish (FIN) AF: 0.707 AC: 7489 AN: 10590

Middle Eastern (MID) AF: 0.521 AC: 152 AN: 292

European-Non Finnish (NFE) AF: 0.597 AC: 40546 AN: 67960

Other (OTH) AF: 0.548 AC: 1157 AN: 2112

Alfa AF: 0.586 Hom.: 12677

Bravo AF: 0.522

Asia WGS AF: 0.591 AC: 2054 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.79
DANN	Benign	0.79
PhyloP100		-0.16
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs7550536; hg19: chr1-12067044; COSMIC: COSV52424175;