11-95845106-C-T

Position:

chr11-95845106-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_016156.6(MTMR2):c.1233G>A(p.Thr411=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0223 in 1,613,806 control chromosomes in the GnomAD database, including 466 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T411T) has been classified as Benign.

Frequency

Genomes: 𝑓 0.016 ( 34 hom., cov: 32)

Exomes 𝑓: 0.023 ( 432 hom. )

Consequence

MTMR2
NM_016156.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -4.40

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.66).

BP6

Variant 11-95845106-C-T is Benign according to our data. Variant chr11-95845106-C-T is described in ClinVar as [Benign]. Clinvar id is 138271.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-95845106-C-T is described in Lovd as [Benign]. Variant chr11-95845106-C-T is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-4.4 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0157 (2392/152288) while in subpopulation NFE AF= 0.0262 (1781/68006). AF 95% confidence interval is 0.0252. There are 34 homozygotes in gnomad4. There are 1069 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 34 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MTMR2	NM_016156.6 linkuse as main transcript	c.1233G>A	p.Thr411=	synonymous_variant	11/15	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.1233G>A	p.Thr411=	synonymous_variant	11/15	1	NM_016156.6	ENSP00000345752	P3	Q13614-1

Frequencies

GnomAD3 genomes

AF:

0.0157

AC:

2392

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00458

Gnomad AMI

AF:

0.00440

Gnomad AMR

AF:

0.00818

Gnomad ASJ

AF:

0.0378

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00249

Gnomad FIN

AF:

0.0106

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0262

Gnomad OTH

AF:

0.0158

GnomAD3 exomes

AF:

0.0167

AC:

4196

AN:

251082

Hom.:

AF XY:

0.0165

AC XY:

2237

AN XY:

135654

show subpopulations

Gnomad AFR exome

AF:

0.00431

Gnomad AMR exome

AF:

0.00727

Gnomad ASJ exome

AF:

0.0365

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00203

Gnomad FIN exome

AF:

0.0132

Gnomad NFE exome

AF:

0.0267

Gnomad OTH exome

AF:

0.0211

GnomAD4 exome

AF:

0.0229

AC:

33522

AN:

1461518

Hom.:

432

Cov.:

AF XY:

0.0224

AC XY:

16319

AN XY:

727050

show subpopulations

Gnomad4 AFR exome

AF:

0.00406

Gnomad4 AMR exome

AF:

0.00857

Gnomad4 ASJ exome

AF:

0.0368

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00225

Gnomad4 FIN exome

AF:

0.0143

Gnomad4 NFE exome

AF:

0.0267

Gnomad4 OTH exome

AF:

0.0220

GnomAD4 genome

AF:

0.0157

AC:

2392

AN:

152288

Hom.:

Cov.:

AF XY:

0.0144

AC XY:

1069

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.00457

Gnomad4 AMR

AF:

0.00817

Gnomad4 ASJ

AF:

0.0378

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00249

Gnomad4 FIN

AF:

0.0106

Gnomad4 NFE

AF:

0.0262

Gnomad4 OTH

AF:

0.0156

Alfa

AF:

0.0253

Hom.:

Bravo

AF:

0.0155

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.0255

EpiControl

AF:

0.0253

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Charcot-Marie-Tooth disease type 4B1

Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 13, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 02, 2017	- -
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 specified

Benign:2

Benign, no assertion criteria provided	literature only	Inherited Neuropathy Consortium	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 23, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Charcot-Marie-Tooth disease

Benign:1

Benign, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

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

BayesDel_noAF

Benign

-0.66

CADD

Benign

0.12

DANN

Benign

0.60

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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