rs142155860

Positions:

chr11-95858554-C-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_016156.6(MTMR2):c.547G>T(p.Ala183Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00216 in 1,611,186 control chromosomes in the GnomAD database, including 73 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0046 ( 17 hom., cov: 32)

Exomes 𝑓: 0.0019 ( 56 hom. )

Consequence

MTMR2
NM_016156.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 7.16

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:

MTMR2 (HGNC:):

MTMR2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009640455).

BP6

Variant 11-95858554-C-A is Benign according to our data. Variant chr11-95858554-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 306544.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1}.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00456 (695/152262) while in subpopulation NFE AF= 0.000926 (63/68002). AF 95% confidence interval is 0.000742. There are 17 homozygotes in gnomad4. There are 530 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MTMR2	NM_016156.6 linkuse as main transcript	c.547G>T	p.Ala183Ser	missense_variant	6/15	ENST00000346299.10	NP_057240.3	Q13614-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MTMR2	ENST00000346299.10 linkuse as main transcript	c.547G>T	p.Ala183Ser	missense_variant	6/15	1	NM_016156.6	ENSP00000345752.6		Q13614-1

Frequencies

GnomAD3 genomes

AF:

0.00457

AC:

695

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0594

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000926

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00474

AC:

1190

AN:

251052

Hom.:

AF XY:

0.00455

AC XY:

617

AN XY:

135696

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0484

Gnomad NFE exome

AF:

0.00103

Gnomad OTH exome

AF:

0.00473

GnomAD4 exome

AF:

0.00191

AC:

2791

AN:

1458924

Hom.:

Cov.:

AF XY:

0.00184

AC XY:

1333

AN XY:

725978

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0458

Gnomad4 NFE exome

AF:

0.000232

Gnomad4 OTH exome

AF:

0.00153

GnomAD4 genome

AF:

0.00456

AC:

695

AN:

152262

Hom.:

Cov.:

AF XY:

0.00712

AC XY:

530

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0594

Gnomad4 NFE

AF:

0.000926

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000466

Hom.:

Bravo

AF:

0.000144

ExAC

AF:

0.00404

AC:

491

EpiCase

AF:

0.000218

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Charcot-Marie-Tooth disease type 4B1

Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Charcot-Marie-Tooth disease type 4

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Uncertain

-0.050

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.64

D;.;.;.;T

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;D;.;.;D

MetaRNN

Benign

0.0096

T;T;T;T;T

MetaSVM

Uncertain

-0.19

MutationAssessor

Uncertain

2.4

M;.;.;.;.

PrimateAI

Uncertain

0.78

PROVEAN

Uncertain

-2.6

D;D;D;D;D

REVEL

Uncertain

0.47

Sift

Benign

0.091

T;T;T;T;T

Sift4G

Benign

0.14

T;T;T;T;.

Polyphen

0.61

P;.;.;.;.

Vest4

0.58

MVP

0.83

MPC

0.50

ClinPred

0.089

GERP RS

5.5

Varity_R

0.56

gMVP

0.78

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

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