Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The ENST00000346299.10(MTMR2):c.1233G>A(p.Thr411Thr) 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
ENST00000346299.10 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -4.40

Publications

4 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 -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 VariationId is 138271.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

BS2

High Homozygotes in GnomAd4 at 34 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000346299.10. 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.1233G>A	p.Thr411Thr	synonymous	Exon 11 of 15	NP_057240.3
MTMR2	NM_001440647.1		c.1149G>A	p.Thr383Thr	synonymous	Exon 10 of 14	NP_001427576.1
MTMR2	NM_001440648.1		c.1233G>A	p.Thr411Thr	synonymous	Exon 11 of 14	NP_001427577.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MTMR2	ENST00000346299.10	TSL:1 MANE Select	c.1233G>A	p.Thr411Thr	synonymous	Exon 11 of 15	ENSP00000345752.6
MTMR2	ENST00000352297.11	TSL:1	c.1017G>A	p.Thr339Thr	synonymous	Exon 12 of 16	ENSP00000343737.7
MTMR2	ENST00000393223.8	TSL:1	c.1017G>A	p.Thr339Thr	synonymous	Exon 12 of 16	ENSP00000376915.3

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

GnomAD2 exomes

AF:

0.0167

AC:

4196

AN:

251082

AF XY:

0.0165

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 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

African (AFR)

AF:

0.00406

AC:

136

AN:

33462

American (AMR)

AF:

0.00857

AC:

383

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.0368

AC:

962

AN:

26128

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39696

South Asian (SAS)

AF:

0.00225

AC:

194

AN:

86258

European-Finnish (FIN)

AF:

0.0143

AC:

763

AN:

53404

Middle Eastern (MID)

AF:

0.00954

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0267

AC:

29697

AN:

1111720

Other (OTH)

AF:

0.0220

AC:

1330

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

1703

3406

5108

6811

8514

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1092

2184

3276

4368

5460

<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:

0.0157

AC:

2392

AN:

152288

Hom.:

Cov.:

AF XY:

0.0144

AC XY:

1069

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.00457

AC:

190

AN:

41570

American (AMR)

AF:

0.00817

AC:

125

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0378

AC:

131

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00249

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0106

AC:

113

AN:

10622

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0262

AC:

1781

AN:

68006

Other (OTH)

AF:

0.0156

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

125

250

374

499

624

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

150

<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:

0.0250

Hom.:

Bravo

AF:

0.0155

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.0255

EpiControl

AF:

0.0253

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Charcot-Marie-Tooth disease type 4B1 (3)

not specified (2)

Charcot-Marie-Tooth disease (1)

Charcot-Marie-Tooth disease type 4 (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.66

CADD

Benign

0.12

(source)

DANN

Benign

0.60

PhyloP100

-4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism (auto)

(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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over