dbSNP rs142155860: MTMR2:p.Ala183Ser (chr11-95858554-C-A) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -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

Publications

5 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: Orphanet, Ambry Genetics, 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 -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 VariationId is 306544.

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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 17 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.547G>T	p.Ala183Ser	missense	Exon 6 of 15	NP_057240.3
MTMR2	NM_001440647.1		c.547G>T	p.Ala183Ser	missense	Exon 6 of 14	NP_001427576.1
MTMR2	NM_001440648.1		c.547G>T	p.Ala183Ser	missense	Exon 6 of 14	NP_001427577.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MTMR2	ENST00000346299.10	TSL:1 MANE Select	c.547G>T	p.Ala183Ser	missense	Exon 6 of 15	ENSP00000345752.6	Q13614-1
MTMR2	ENST00000352297.11	TSL:1	c.331G>T	p.Ala111Ser	missense	Exon 7 of 16	ENSP00000343737.7	Q13614-2
MTMR2	ENST00000393223.8	TSL:1	c.331G>T	p.Ala111Ser	missense	Exon 7 of 16	ENSP00000376915.3	Q13614-2

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

GnomAD2 exomes

AF:

0.00474

AC:

1190

AN:

251052

AF XY:

0.00455

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 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

African (AFR)

AF:

0.0000299

AC:

AN:

33390

American (AMR)

AF:

0.0000224

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26098

East Asian (EAS)

AF:

0.00

AC:

AN:

39584

South Asian (SAS)

AF:

0.00

AC:

AN:

86206

European-Finnish (FIN)

AF:

0.0458

AC:

2440

AN:

53232

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.000232

AC:

257

AN:

1109658

Other (OTH)

AF:

0.00153

AC:

AN:

60276

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

Heterozygous variant carriers

133

266

398

531

664

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.00456

AC:

695

AN:

152262

Hom.:

Cov.:

AF XY:

0.00712

AC XY:

530

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41562

American (AMR)

AF:

0.00

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0594

AC:

630

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000926

AC:

AN:

68002

Other (OTH)

AF:

0.000473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

106

141

176

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:

0.000601

Hom.:

Bravo

AF:

0.000144

ExAC

AF:

0.00404

AC:

491

EpiCase

AF:

0.000218

EpiControl

AF:

0.000119

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Charcot-Marie-Tooth disease type 4 (1)

Charcot-Marie-Tooth disease type 4B1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Uncertain

-0.050

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.64

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

MetaRNN

Benign

0.0096

MetaSVM

Uncertain

-0.19

MutationAssessor

Uncertain

2.4

PhyloP100

7.2

PrimateAI

Uncertain

0.78

PROVEAN

Uncertain

-2.6

REVEL

Uncertain

0.47

Sift

Benign

0.091

Sift4G

Benign

0.14

Polyphen

0.61

Vest4

0.58

MVP

0.83

MPC

0.50

ClinPred

0.089

GERP RS

5.5

Varity_R

0.56

gMVP

0.78

Mutation Taster

=87/13

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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

Computational scores

Splicing

Publications

Other links and lift over