rs886048770

Variant names:

• chr11-95835379-G-A
• rs886048770
• NM_016156.6:c.1843C>T

Your query was ambiguous. Multiple possible variants found:

• chr11-95835379-G-A
• chr11-95835379-G-C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The NM_016156.6(MTMR2):​c.1843C>T​(p.Gln615*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000411 in 1,460,964 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: MTMR2 NM_016156.6 stop_gained
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.28
• 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: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 4 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTMR2	NM_016156.6	MANE Select	c.1843C>T	p.Gln615*	stop_gained	Exon 15 of 15	NP_057240.3
	MTMR2	NM_001440647.1		c.1759C>T	p.Gln587*	stop_gained	Exon 14 of 14	NP_001427576.1
	MTMR2	NM_001440648.1		c.1750C>T	p.Gln584*	stop_gained	Exon 14 of 14	NP_001427577.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTMR2	ENST00000346299.10	TSL:1 MANE Select	c.1843C>T	p.Gln615*	stop_gained	Exon 15 of 15	ENSP00000345752.6	Q13614-1
	MTMR2	ENST00000352297.11	TSL:1	c.1627C>T	p.Gln543*	stop_gained	Exon 16 of 16	ENSP00000343737.7	Q13614-2
	MTMR2	ENST00000393223.8	TSL:1	c.1627C>T	p.Gln543*	stop_gained	Exon 16 of 16	ENSP00000376915.3	Q13614-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1460964 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 726784

African (AFR) AF: 0.00 AC: 0 AN: 33448

American (AMR) AF: 0.00 AC: 0 AN: 44610

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26100

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53382

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111402

Other (OTH) AF: 0.00 AC: 0 AN: 60344

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000312 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Charcot-Marie-Tooth disease type 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.61	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	44
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		6.3
Vest4		0.79
GERP RS		6.2
Mutation Taster		=6/194	disease causing

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: rs886048770; hg19: chr11-95568543; COSMIC: COSV57687420; COSMIC: COSV57687420;