11-95923947-T-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_016156.6(MTMR2):c.8A>C(p.Lys3Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.355 in 1,557,506 control chromosomes in the GnomAD database, including 103,642 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K3R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.28 ( 7360 hom., cov: 33)

Exomes 𝑓: 0.36 ( 96282 hom. )

Consequence

MTMR2
NM_016156.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 1.46

Publications

44 publications found

Variant links:

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)

MTMR2 links:

ENSG00000295552 (HGNC:):

ENSG00000295552 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.0020042658).

BP6

Variant 11-95923947-T-G is Benign according to our data. Variant chr11-95923947-T-G is described in ClinVar as [Benign]. Clinvar id is 260686.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.386 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTMR2	NM_016156.6 link	c.8A>C	p.Lys3Thr	missense_variant	Exon 1 of 15	ENST00000346299.10	NP_057240.3	Q13614-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTMR2	ENST00000346299.10 link	c.8A>C	p.Lys3Thr	missense_variant	Exon 1 of 15	1	NM_016156.6	ENSP00000345752.6		Q13614-1

Frequencies

GnomAD3 genomes

AF:

0.284

AC:

43157

AN:

152070

Hom.:

7358

Cov.:

show subpopulations

Gnomad AFR

AF:

0.109

Gnomad AMI

AF:

0.353

Gnomad AMR

AF:

0.272

Gnomad ASJ

AF:

0.532

Gnomad EAS

AF:

0.280

Gnomad SAS

AF:

0.168

Gnomad FIN

AF:

0.260

Gnomad MID

AF:

0.272

Gnomad NFE

AF:

0.390

Gnomad OTH

AF:

0.331

GnomAD2 exomes

AF:

0.288

AC:

46351

AN:

160886

AF XY:

0.288

show subpopulations

Gnomad AFR exome

AF:

0.0941

Gnomad AMR exome

AF:

0.209

Gnomad ASJ exome

AF:

0.521

Gnomad EAS exome

AF:

0.268

Gnomad FIN exome

AF:

0.259

Gnomad NFE exome

AF:

0.365

Gnomad OTH exome

AF:

0.356

GnomAD4 exome

AF:

0.362

AC:

509240

AN:

1405318

Hom.:

96282

Cov.:

AF XY:

0.357

AC XY:

247845

AN XY:

693846

show subpopulations

African (AFR)

AF:

0.101

AC:

3227

AN:

32048

American (AMR)

AF:

0.220

AC:

8133

AN:

36970

Ashkenazi Jewish (ASJ)

AF:

0.522

AC:

13138

AN:

25192

East Asian (EAS)

AF:

0.319

AC:

11567

AN:

36224

South Asian (SAS)

AF:

0.177

AC:

14144

AN:

79942

European-Finnish (FIN)

AF:

0.263

AC:

12935

AN:

49166

Middle Eastern (MID)

AF:

0.303

AC:

1699

AN:

5606

European-Non Finnish (NFE)

AF:

0.392

AC:

423851

AN:

1081948

Other (OTH)

AF:

0.353

AC:

20546

AN:

58222

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

Heterozygous variant carriers

15462

30925

46387

61850

77312

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13192

26384

39576

52768

65960

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.284

AC:

43159

AN:

152188

Hom.:

7360

Cov.:

AF XY:

0.275

AC XY:

20474

AN XY:

74404

show subpopulations

African (AFR)

AF:

0.109

AC:

4513

AN:

41560

American (AMR)

AF:

0.272

AC:

4155

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.532

AC:

1846

AN:

3472

East Asian (EAS)

AF:

0.281

AC:

1453

AN:

5176

South Asian (SAS)

AF:

0.167

AC:

807

AN:

4824

European-Finnish (FIN)

AF:

0.260

AC:

2757

AN:

10594

Middle Eastern (MID)

AF:

0.276

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.390

AC:

26514

AN:

67944

Other (OTH)

AF:

0.336

AC:

711

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1509

3018

4526

6035

7544

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

434

868

1302

1736

2170

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.349

Hom.:

16124

Bravo

AF:

0.281

TwinsUK

AF:

0.394

AC:

1460

ALSPAC

AF:

0.395

AC:

1524

ESP6500AA

AF:

0.0895

AC:

384

ESP6500EA

AF:

0.317

AC:

2643

ExAC

AF:

0.132

AC:

13896

Asia WGS

AF:

0.227

AC:

790

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Charcot-Marie-Tooth disease type 4B1

Benign:4

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Jun 02, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Charcot-Marie-Tooth disease

Benign:1

Molecular Genetics Laboratory, London Health Sciences Centre

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Charcot-Marie-Tooth disease type 4

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.13

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.45

Eigen

Benign

-0.55

Eigen_PC

Benign

-0.48

FATHMM_MKL

Benign

0.32

LIST_S2

Benign

0.59

MetaRNN

Benign

0.0020

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.3

PhyloP100

1.5

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

-0.99

REVEL

Uncertain

0.32

Sift

Uncertain

0.010

Sift4G

Benign

0.13

Polyphen

0.039

Vest4

0.10

MPC

0.40

ClinPred

0.042

GERP RS

0.82

PromoterAI

0.0088

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.22

gMVP

0.40

Mutation Taster

=97/3

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over