11-95923947-T-G

Position:

chr11-95923947-T-G

Variant summary

Our verdict is Benign. Variant got -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. 12/20 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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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. Variant chr11-95923947-T-G is described in Lovd as [Benign].

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/exons	MANE
MTMR2	NM_016156.6 linkuse as main transcript	c.8A>C	p.Lys3Thr	missense_variant	1/15	ENST00000346299.10
MTMR2	NM_001243571.2 linkuse as main transcript	c.-476A>C		5_prime_UTR_variant	1/18
MTMR2	NM_201278.3 linkuse as main transcript	c.-403A>C		5_prime_UTR_variant	1/17
MTMR2	NM_201281.3 linkuse as main transcript	c.-280A>C		5_prime_UTR_variant	1/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTMR2	ENST00000346299.10 linkuse as main transcript	c.8A>C	p.Lys3Thr	missense_variant	1/15	1	NM_016156.6	P3	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

GnomAD3 exomes

AF:

0.288

AC:

46351

AN:

160886

Hom.:

7852

AF XY:

0.288

AC XY:

24838

AN XY:

86292

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 SAS exome

AF:

0.174

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

Gnomad4 AFR exome

AF:

0.101

Gnomad4 AMR exome

AF:

0.220

Gnomad4 ASJ exome

AF:

0.522

Gnomad4 EAS exome

AF:

0.319

Gnomad4 SAS exome

AF:

0.177

Gnomad4 FIN exome

AF:

0.263

Gnomad4 NFE exome

AF:

0.392

Gnomad4 OTH exome

AF:

0.353

GnomAD4 genome

AF:

0.284

AC:

43159

AN:

152188

Hom.:

7360

Cov.:

AF XY:

0.275

AC XY:

20474

AN XY:

74404

show subpopulations

Gnomad4 AFR

AF:

0.109

Gnomad4 AMR

AF:

0.272

Gnomad4 ASJ

AF:

0.532

Gnomad4 EAS

AF:

0.281

Gnomad4 SAS

AF:

0.167

Gnomad4 FIN

AF:

0.260

Gnomad4 NFE

AF:

0.390

Gnomad4 OTH

AF:

0.336

Alfa

AF:

0.362

Hom.:

12876

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

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 02, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Charcot-Marie-Tooth disease

Benign:1

Benign, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

- -

Charcot-Marie-Tooth disease type 4

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

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

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

MutationTaster

Benign

0.51

P;P;P;P

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

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.22

gMVP

0.40

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over