1-11980347-C-T

Variant names:

• chr1-11980347-C-T
• rs2180181
• ENST00000675298.1:c.-287C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000444836.5(MFN2):​c.-142C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00672 in 398,336 control chromosomes in the GnomAD database, including 67 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (53 hom., cov: 33)
  • Exomes 𝑓: 0.0020 (14 hom.)
• Consequence: MFN2 ENST00000444836.5 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.558
• Publications: 2 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: G2P, Labcorp Genetics (formerly Invitae)
• multiple symmetric lipomatosis with partial lipodystrophy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• 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

ENSG00000287384 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 1-11980347-C-T is Benign according to our data. Variant chr1-11980347-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 292365.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0144 (2193/152300) while in subpopulation AFR AF = 0.0493 (2049/41560). AF 95% confidence interval is 0.0475. There are 53 homozygotes in GnomAd4. There are 1001 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 53 AD,AR,SD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000444836.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MFN2	NM_014874.4	MANE Select	c.-287C>T		upstream_gene	N/A	NP_055689.1	O95140-1
	MFN2	NM_001127660.2		c.-142C>T		upstream_gene	N/A	NP_001121132.1	O95140-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MFN2	ENST00000675298.1		c.-287C>T		5_prime_UTR	Exon 1 of 19	ENSP00000501839.1	A0A6Q8PFJ4
	MFN2	ENST00000675817.1		c.-287C>T		5_prime_UTR	Exon 1 of 20	ENSP00000502422.1	A0A6Q8PGV8
	MFN2	ENST00000898885.1		c.-287C>T		5_prime_UTR	Exon 1 of 20	ENSP00000568944.1

Frequencies

GnomAD3 genomes AF: 0.0144 AC: 2187 AN: 152182 Hom.: 53 Cov.: 33

Gnomad AFR AF: 0.0493

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00752

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00861

GnomAD4 exome AF: 0.00196 AC: 482 AN: 246036 Hom.: 14 Cov.: 0 AF XY: 0.00150 AC XY: 187 AN XY: 124738

African (AFR) AF: 0.0486 AC: 348 AN: 7162

American (AMR) AF: 0.00593 AC: 44 AN: 7422

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9218

East Asian (EAS) AF: 0.00 AC: 0 AN: 22888

South Asian (SAS) AF: 0.00 AC: 0 AN: 3036

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 20830

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1294

European-Non Finnish (NFE) AF: 0.0000824 AC: 13 AN: 157840

Other (OTH) AF: 0.00471 AC: 77 AN: 16346

GnomAD4 genome AF: 0.0144 AC: 2193 AN: 152300 Hom.: 53 Cov.: 33 AF XY: 0.0134 AC XY: 1001 AN XY: 74476

African (AFR) AF: 0.0493 AC: 2049 AN: 41560

American (AMR) AF: 0.00745 AC: 114 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68018

Other (OTH) AF: 0.00852 AC: 18 AN: 2112

Alfa AF: 0.00440 Hom.: 1

Bravo AF: 0.0169

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Charcot-Marie-Tooth disease type 2 (1)
-	-	1	Hereditary motor and sensory neuropathy (1)
-	-	1	Hereditary motor and sensory neuropathy with optic atrophy (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.5
DANN	Benign	0.89
PhyloP100		-0.56
PromoterAI		0.032	Neutral
Mutation Taster		=299/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs2180181; hg19: chr1-12040404;