11-95835367-A-G

Position:

chr11-95835367-A-G

Variant summary

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

The NM_016156.6(MTMR2):c.1855T>C(p.Ser619Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00212 in 1,613,144 control chromosomes in the GnomAD database, including 24 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 0.0020 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0021 ( 22 hom. )

Consequence

MTMR2
NM_016156.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:9

Conservation

PhyloP100: 1.28

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0077272058).

BP6

Variant 11-95835367-A-G is Benign according to our data. Variant chr11-95835367-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 234375.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=5, Uncertain_significance=1}. Variant chr11-95835367-A-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00202 (308/152162) while in subpopulation SAS AF= 0.0133 (64/4828). AF 95% confidence interval is 0.0107. There are 2 homozygotes in gnomad4. There are 154 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MTMR2	NM_016156.6 linkuse as main transcript	c.1855T>C	p.Ser619Pro	missense_variant	15/15	ENST00000346299.10	NP_057240.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MTMR2	ENST00000346299.10 linkuse as main transcript	c.1855T>C	p.Ser619Pro	missense_variant	15/15	1	NM_016156.6	ENSP00000345752	P3	Q13614-1

Frequencies

GnomAD3 genomes

AF:

0.00202

AC:

307

AN:

152044

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000386

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00204

Gnomad ASJ

AF:

0.00548

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0130

Gnomad FIN

AF:

0.000847

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00240

Gnomad OTH

AF:

0.000958

GnomAD3 exomes

AF:

0.00278

AC:

696

AN:

250592

Hom.:

AF XY:

0.00326

AC XY:

442

AN XY:

135422

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.000987

Gnomad ASJ exome

AF:

0.00318

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00967

Gnomad FIN exome

AF:

0.00204

Gnomad NFE exome

AF:

0.00234

Gnomad OTH exome

AF:

0.00311

GnomAD4 exome

AF:

0.00213

AC:

3119

AN:

1460982

Hom.:

Cov.:

AF XY:

0.00251

AC XY:

1821

AN XY:

726788

show subpopulations

Gnomad4 AFR exome

AF:

0.000239

Gnomad4 AMR exome

AF:

0.00128

Gnomad4 ASJ exome

AF:

0.00333

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00983

Gnomad4 FIN exome

AF:

0.00208

Gnomad4 NFE exome

AF:

0.00164

Gnomad4 OTH exome

AF:

0.00242

GnomAD4 genome

AF:

0.00202

AC:

308

AN:

152162

Hom.:

Cov.:

AF XY:

0.00207

AC XY:

154

AN XY:

74414

show subpopulations

Gnomad4 AFR

AF:

0.000385

Gnomad4 AMR

AF:

0.00203

Gnomad4 ASJ

AF:

0.00548

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0133

Gnomad4 FIN

AF:

0.000847

Gnomad4 NFE

AF:

0.00240

Gnomad4 OTH

AF:

0.000948

Alfa

AF:

0.00199

Hom.:

Bravo

AF:

0.00170

TwinsUK

AF:

0.00216

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00244

AC:

ExAC

AF:

0.00302

AC:

367

Asia WGS

AF:

0.00433

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:9

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:5

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	MTMR2: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 10, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 17, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Charcot-Marie-Tooth disease type 4B1

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 18, 2022	- -

Charcot-Marie-Tooth disease

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

- -

MTMR2-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 25, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Charcot-Marie-Tooth disease type 4

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Uncertain

-0.010

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.49

T;.;.;.;T

Eigen

Benign

-0.035

Eigen_PC

Benign

0.16

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.91

D;D;.;.;D

MetaRNN

Benign

0.0077

T;T;T;T;T

MetaSVM

Uncertain

0.19

MutationAssessor

Benign

1.7

L;.;.;.;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-2.3

N;N;N;N;N

REVEL

Uncertain

0.37

Sift

Benign

0.069

T;T;T;T;T

Sift4G

Benign

0.25

T;T;T;T;.

Polyphen

0.0020

B;.;.;.;.

Vest4

0.13

MVP

0.94

MPC

0.47

ClinPred

0.024

GERP RS

6.2

Varity_R

0.34

gMVP

0.56

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