rs687559

Variant names:

• chr11-95865465-A-G
• rs687559
• NM_016156.6:c.262+136T>C

Variant summary

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

The NM_001440642.1(MTMR2):​c.-112T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.528 in 834,660 control chromosomes in the GnomAD database, including 120,970 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.60 (29265 hom., cov: 31)
  • Exomes 𝑓: 0.51 (91705 hom.)
• Consequence: MTMR2 NM_001440642.1 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.48
• Publications: 10 publications found

Genes affected

MTMR2 (HGNC:7450): (myotubularin related protein 2) This gene is a member of the myotubularin family of phosphoinositide lipid phosphatases. The encoded protein possesses phosphatase activity towards phosphatidylinositol-3-phosphate and phosphatidylinositol-3,5-bisphosphate. Mutations in this gene are a cause of Charcot-Marie-Tooth disease type 4B, an autosomal recessive demyelinating neuropathy. Alternatively spliced transcript variants encoding multiple isoforms have been found for this gene. [provided by RefSeq, Aug 2011]

MTMR2 Gene-Disease associations (from GenCC):

• demyelinating hereditary motor and sensory neuropathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Charcot-Marie-Tooth disease type 4B1

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 11-95865465-A-G is Benign according to our data. Variant chr11-95865465-A-G is described in ClinVar as Benign. ClinVar VariationId is 683213.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.841 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001440642.1. 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
	MTMR2	NM_016156.6	MANE Select	c.262+136T>C		intron	N/A	NP_057240.3
	MTMR2	NM_001440642.1		c.-112T>C		5_prime_UTR	Exon 3 of 15	NP_001427571.1
	MTMR2	NM_001440647.1		c.262+136T>C		intron	N/A	NP_001427576.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTMR2	ENST00000346299.10	TSL:1 MANE Select	c.262+136T>C		intron	N/A	ENSP00000345752.6
	MTMR2	ENST00000352297.11	TSL:1	c.46+136T>C		intron	N/A	ENSP00000343737.7
	MTMR2	ENST00000393223.8	TSL:1	c.46+136T>C		intron	N/A	ENSP00000376915.3

Frequencies

GnomAD3 genomes AF: 0.598 AC: 90890 AN: 151906 Hom.: 29207 Cov.: 31

Gnomad AFR AF: 0.849

Gnomad AMI AF: 0.400

Gnomad AMR AF: 0.523

Gnomad ASJ AF: 0.673

Gnomad EAS AF: 0.391

Gnomad SAS AF: 0.449

Gnomad FIN AF: 0.489

Gnomad MID AF: 0.608

Gnomad NFE AF: 0.505

Gnomad OTH AF: 0.601

GnomAD4 exome AF: 0.513 AC: 349875 AN: 682634 Hom.: 91705 Cov.: 9 AF XY: 0.509 AC XY: 186688 AN XY: 366740

African (AFR) AF: 0.851 AC: 15721 AN: 18476

American (AMR) AF: 0.491 AC: 20285 AN: 41296

Ashkenazi Jewish (ASJ) AF: 0.682 AC: 14207 AN: 20832

East Asian (EAS) AF: 0.434 AC: 15526 AN: 35740

South Asian (SAS) AF: 0.460 AC: 31719 AN: 69028

European-Finnish (FIN) AF: 0.481 AC: 24162 AN: 50218

Middle Eastern (MID) AF: 0.584 AC: 2457 AN: 4204

European-Non Finnish (NFE) AF: 0.507 AC: 206937 AN: 408178

Other (OTH) AF: 0.544 AC: 18861 AN: 34662

GnomAD4 genome AF: 0.599 AC: 91006 AN: 152026 Hom.: 29265 Cov.: 31 AF XY: 0.593 AC XY: 44031 AN XY: 74308

African (AFR) AF: 0.849 AC: 35209 AN: 41486

American (AMR) AF: 0.522 AC: 7967 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.673 AC: 2335 AN: 3470

East Asian (EAS) AF: 0.392 AC: 2027 AN: 5172

South Asian (SAS) AF: 0.448 AC: 2159 AN: 4818

European-Finnish (FIN) AF: 0.489 AC: 5167 AN: 10572

Middle Eastern (MID) AF: 0.619 AC: 182 AN: 294

European-Non Finnish (NFE) AF: 0.505 AC: 34318 AN: 67942

Other (OTH) AF: 0.606 AC: 1279 AN: 2112

Alfa AF: 0.547 Hom.: 8858

Bravo AF: 0.615

Asia WGS AF: 0.438 AC: 1523 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	-0.95
CADD	Benign	7.0
DANN	Benign	0.42
PhyloP100		1.5
PromoterAI		0.0073	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs687559; hg19: chr11-95598629; COSMIC: COSV60578875; COSMIC: COSV60578875;