chr11-95923939-T-A

Position:

chr11-95923939-T-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 4P and 5B. PM1PM2BP4_StrongBS1_Supporting

The NM_016156.6(MTMR2):c.16A>T(p.Ser6Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000948 in 1,560,562 control chromosomes in the GnomAD database, including 1 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 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000092 ( 1 hom. )

Consequence

MTMR2
NM_016156.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:1

Conservation

PhyloP100: 3.66

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 Likely_benign. Variant got -1 ACMG points.

PM1

In a modified_residue Phosphoserine (size 0) in uniprot entity MTMR2_HUMAN

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.043688923).

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0000916 (129/1408342) while in subpopulation MID AF= 0.00177 (10/5642). AF 95% confidence interval is 0.000962. There are 1 homozygotes in gnomad4_exome. There are 69 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MTMR2	NM_016156.6 linkuse as main transcript	c.16A>T	p.Ser6Cys	missense_variant	1/15	ENST00000346299.10	NP_057240.3	Q13614-1
MTMR2	NM_001243571.2 linkuse as main transcript	c.-468A>T		5_prime_UTR_variant	1/18		NP_001230500.1	Q13614-2A0A024R3B7
MTMR2	NM_201278.3 linkuse as main transcript	c.-395A>T		5_prime_UTR_variant	1/17		NP_958435.1	Q13614-2A0A024R3B7
MTMR2	NM_201281.3 linkuse as main transcript	c.-272A>T		5_prime_UTR_variant	1/16		NP_958438.1	Q13614-2A0A024R3B7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MTMR2	ENST00000346299.10 linkuse as main transcript	c.16A>T	p.Ser6Cys	missense_variant	1/15	1	NM_016156.6	ENSP00000345752.6		Q13614-1

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000654

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000197

AC:

AN:

162472

Hom.:

AF XY:

0.000183

AC XY:

AN XY:

87270

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000614

Gnomad ASJ exome

AF:

0.000939

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000848

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000787

Gnomad OTH exome

AF:

0.000222

GnomAD4 exome

AF:

0.0000916

AC:

129

AN:

1408342

Hom.:

Cov.:

AF XY:

0.0000992

AC XY:

AN XY:

695598

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000456

Gnomad4 ASJ exome

AF:

0.00127

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000499

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000554

Gnomad4 OTH exome

AF:

0.000103

GnomAD4 genome

AF:

0.000125

AC:

AN:

152220

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74370

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000654

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000158

Hom.:

Bravo

AF:

0.000174

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000120

AC:

ExAC

AF:

0.000144

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 28, 2023	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 09, 2019	- -

Charcot-Marie-Tooth disease

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 04, 2023

The c.16A>T (p.S6C) alteration is located in exon 1 (coding exon 1) of the MTMR2 gene. This alteration results from a A to T substitution at nucleotide position 16, causing the serine (S) at amino acid position 6 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Charcot-Marie-Tooth disease type 4

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 18, 2022

This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 6 of the MTMR2 protein (p.Ser6Cys). This variant is present in population databases (rs377006678, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with MTMR2-related conditions. ClinVar contains an entry for this variant (Variation ID: 476870). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Charcot-Marie-Tooth disease type 4B1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 26, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.058

BayesDel_noAF

Uncertain

0.040

CADD

Uncertain

DANN

Uncertain

0.97

DEOGEN2

Uncertain

0.45

Eigen

Benign

0.033

Eigen_PC

Benign

0.051

FATHMM_MKL

Benign

0.50

LIST_S2

Benign

0.83

M_CAP

Pathogenic

0.54

MetaRNN

Benign

0.044

MetaSVM

Uncertain

0.35

MutationAssessor

Benign

1.3

PrimateAI

Pathogenic

0.79

PROVEAN

Benign

-1.3

REVEL

Uncertain

0.44

Sift

Uncertain

0.0040

Sift4G

Uncertain

0.019

Polyphen

0.89

Vest4

0.42

MVP

0.93

MPC

0.46

ClinPred

0.17

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.27

gMVP

0.63

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