rs1555057316

Variant names:

• chr11-95838148-G-GTA
• rs1555057316
• NM_016156.6:c.1537_1538dupTA

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_016156.6(MTMR2):​c.1537_1538dupTA​(p.Ser514ThrfsTer32) variant causes a frameshift change. The variant allele was found at a frequency of 0.000000685 in 1,459,618 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: MTMR2 NM_016156.6 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 6.13
• Publications: 0 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: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-95838148-G-GTA is Pathogenic according to our data. Variant chr11-95838148-G-GTA is described in ClinVar as Pathogenic. ClinVar VariationId is 406679.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016156.6. 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.1537_1538dupTA	p.Ser514ThrfsTer32	frameshift	Exon 13 of 15	NP_057240.3
	MTMR2	NM_001440647.1		c.1453_1454dupTA	p.Ser486ThrfsTer32	frameshift	Exon 12 of 14	NP_001427576.1
	MTMR2	NM_001440648.1		c.1444_1445dupTA	p.Ser483ThrfsTer32	frameshift	Exon 12 of 14	NP_001427577.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTMR2	ENST00000346299.10	TSL:1 MANE Select	c.1537_1538dupTA	p.Ser514ThrfsTer32	frameshift	Exon 13 of 15	ENSP00000345752.6
	MTMR2	ENST00000352297.11	TSL:1	c.1321_1322dupTA	p.Ser442ThrfsTer32	frameshift	Exon 14 of 16	ENSP00000343737.7
	MTMR2	ENST00000393223.8	TSL:1	c.1321_1322dupTA	p.Ser442ThrfsTer32	frameshift	Exon 14 of 16	ENSP00000376915.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459618 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726216

African (AFR) AF: 0.00 AC: 0 AN: 33382

American (AMR) AF: 0.0000224 AC: 1 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26074

East Asian (EAS) AF: 0.00 AC: 0 AN: 39632

South Asian (SAS) AF: 0.00 AC: 0 AN: 86228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53364

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110208

Other (OTH) AF: 0.00 AC: 0 AN: 60286

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Charcot-Marie-Tooth disease type 4B1 Pathogenic:1

Nov 05, 2018

Knight Diagnostic Laboratories, Oregon Health and Sciences University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Charcot-Marie-Tooth disease type 4 Pathogenic:1

Mar 05, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been reported in the literature in individuals with MTMR2-related conditions. For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in MTMR2 are known to be pathogenic (PMID: 10802647). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Ser514Thrfs*32) in the MTMR2 gene. It is expected to result in an absent or disrupted protein product.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.1
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1555057316; hg19: chr11-95571312;