dbSNP rs574213477: MTMR2:c.-232C>T (chr11-95923899-G-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_201278.3(MTMR2):c.-355C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000121 in 1,557,868 control chromosomes in the GnomAD database, including 2 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 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00013 ( 2 hom. )

Consequence

MTMR2
NM_201278.3 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: 0.709

Publications

1 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:

ENSG00000295552 (HGNC:):

ENSG00000295552 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=0.009596497).

BP6

Variant 11-95923899-G-A is Benign according to our data. Variant chr11-95923899-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 234848.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0000656 (10/152370) while in subpopulation SAS AF = 0.00207 (10/4834). AF 95% confidence interval is 0.00112. There are 0 homozygotes in GnomAd4. There are 9 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_201278.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MTMR2	NM_016156.6	MANE Select	c.56C>T	p.Pro19Leu	missense	Exon 1 of 15	NP_057240.3
MTMR2	NM_001243571.2		c.-428C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 18	NP_001230500.1	Q13614-2
MTMR2	NM_001440631.1		c.-512C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 19	NP_001427560.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MTMR2	ENST00000352297.11	TSL:1	c.-232C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 16	ENSP00000343737.7	Q13614-2
MTMR2	ENST00000393223.8	TSL:1	c.-253C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 16	ENSP00000376915.3	Q13614-2
MTMR2	ENST00000346299.10	TSL:1 MANE Select	c.56C>T	p.Pro19Leu	missense	Exon 1 of 15	ENSP00000345752.6	Q13614-1

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152252

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000304

AC:

AN:

157720

AF XY:

0.000412

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000330

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000127

AC:

178

AN:

1405498

Hom.:

Cov.:

AF XY:

0.000173

AC XY:

120

AN XY:

693958

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32016

American (AMR)

AF:

0.00

AC:

AN:

36730

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25214

East Asian (EAS)

AF:

0.00

AC:

AN:

36194

South Asian (SAS)

AF:

0.00192

AC:

153

AN:

79816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48794

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5662

European-Non Finnish (NFE)

AF:

0.00000831

AC:

AN:

1082802

Other (OTH)

AF:

0.000275

AC:

AN:

58270

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

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:

0.0000656

AC:

AN:

152370

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74512

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41598

American (AMR)

AF:

0.00

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00207

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.000155

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Charcot-Marie-Tooth disease (1)

Charcot-Marie-Tooth disease type 4 (1)

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.22

CADD

Benign

(source)

DANN

Benign

0.88

DEOGEN2

Benign

0.29

Eigen

Benign

-0.65

Eigen_PC

Benign

-0.46

FATHMM_MKL

Benign

0.24

LIST_S2

Benign

0.74

M_CAP

Uncertain

0.23

MetaRNN

Benign

0.0096

MetaSVM

Benign

-0.42

MutationAssessor

Benign

-0.69

PhyloP100

0.71

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-0.64

REVEL

Benign

0.28

Sift

Benign

0.66

Sift4G

Benign

0.69

Polyphen

0.0

Vest4

0.14

MutPred

0.13

Loss of catalytic residue at P19 (P = 0.0189)

MVP

0.86

MPC

0.33

ClinPred

0.065

GERP RS

3.6

PromoterAI

-0.057

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.7

Varity_R

0.031

gMVP

0.39

Mutation Taster

=94/6

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

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