Genetic Variant MTMR2:p.Ala602Gly (chr11-95835417-G-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_016156.6(MTMR2):c.1805C>G(p.Ala602Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000849 in 1,613,024 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0010 ( 2 hom., cov: 32)

Exomes 𝑓: 0.00083 ( 30 hom. )

Consequence

MTMR2
NM_016156.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:5

Conservation

PhyloP100: 7.73

Publications

8 publications found

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 Gene-Disease associations (from GenCC):

demyelinating hereditary motor and sensory neuropathy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
Charcot-Marie-Tooth disease type 4B1
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)

MTMR2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008868843).

BP6

Variant 11-95835417-G-C is Benign according to our data. Variant chr11-95835417-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 306535.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000999 (152/152186) while in subpopulation EAS AF = 0.0276 (143/5182). AF 95% confidence interval is 0.0239. There are 2 homozygotes in GnomAd4. There are 85 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016156.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MTMR2	NM_016156.6	MANE Select	c.1805C>G	p.Ala602Gly	missense	Exon 15 of 15	NP_057240.3
MTMR2	NM_001440647.1		c.1721C>G	p.Ala574Gly	missense	Exon 14 of 14	NP_001427576.1
MTMR2	NM_001440648.1		c.1712C>G	p.Ala571Gly	missense	Exon 14 of 14	NP_001427577.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MTMR2	ENST00000346299.10	TSL:1 MANE Select	c.1805C>G	p.Ala602Gly	missense	Exon 15 of 15	ENSP00000345752.6
MTMR2	ENST00000352297.11	TSL:1	c.1589C>G	p.Ala530Gly	missense	Exon 16 of 16	ENSP00000343737.7
MTMR2	ENST00000393223.8	TSL:1	c.1589C>G	p.Ala530Gly	missense	Exon 16 of 16	ENSP00000376915.3

Frequencies

GnomAD3 genomes

AF:

0.00100

AC:

152

AN:

152068

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0275

Gnomad SAS

AF:

0.000827

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.00212

AC:

531

AN:

250250

AF XY:

0.00185

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0280

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.000981

GnomAD4 exome

AF:

0.000833

AC:

1217

AN:

1460838

Hom.:

Cov.:

AF XY:

0.000794

AC XY:

577

AN XY:

726732

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33444

American (AMR)

AF:

0.0000224

AC:

AN:

44642

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26104

East Asian (EAS)

AF:

0.0277

AC:

1099

AN:

39684

South Asian (SAS)

AF:

0.000325

AC:

AN:

86232

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53398

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5692

European-Non Finnish (NFE)

AF:

0.00000810

AC:

AN:

1111306

Other (OTH)

AF:

0.00133

AC:

AN:

60336

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

138

206

275

344

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000999

AC:

152

AN:

152186

Hom.:

Cov.:

AF XY:

0.00114

AC XY:

AN XY:

74420

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41554

American (AMR)

AF:

0.000131

AC:

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.0276

AC:

143

AN:

5182

South Asian (SAS)

AF:

0.000828

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

67960

Other (OTH)

AF:

0.000474

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00121

Hom.:

Bravo

AF:

0.00104

ExAC

AF:

0.00221

AC:

268

Asia WGS

AF:

0.00462

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Charcot-Marie-Tooth disease type 4B1

Benign:2

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

Jul 25, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Charcot-Marie-Tooth disease

Uncertain:1

Inherited Neuropathy Consortium

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:literature only

not specified

Benign:1

Feb 08, 2017

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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.

not provided

Benign:1

Mar 11, 2020

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Charcot-Marie-Tooth disease type 4

Benign:1

Jan 08, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Uncertain

0.070

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.56

Eigen

Uncertain

0.30

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

MetaRNN

Benign

0.0089

MetaSVM

Uncertain

0.14

MutationAssessor

Uncertain

2.5

PhyloP100

7.7

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-2.2

REVEL

Uncertain

0.42

Sift

Benign

0.084

Sift4G

Benign

0.33

Polyphen

0.14

Vest4

0.45

MVP

0.95

MPC

0.42

ClinPred

0.061

GERP RS

6.2

Varity_R

0.30

gMVP

0.39

Mutation Taster

=73/27

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over