rs371925152

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_016156.6(MTMR2):ā€‹c.1862G>Cā€‹(p.Arg621Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000821 in 1,460,924 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 0.0000082 ( 0 hom. )

Consequence

MTMR2
NM_016156.6 missense

Scores

3
14
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.74
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MTMR2NM_016156.6 linkuse as main transcriptc.1862G>C p.Arg621Pro missense_variant 15/15 ENST00000346299.10 NP_057240.3 Q13614-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MTMR2ENST00000346299.10 linkuse as main transcriptc.1862G>C p.Arg621Pro missense_variant 15/151 NM_016156.6 ENSP00000345752.6 Q13614-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.0000160
AC:
4
AN:
250492
Hom.:
0
AF XY:
0.0000222
AC XY:
3
AN XY:
135374
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000163
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000884
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000821
AC:
12
AN:
1460924
Hom.:
0
Cov.:
31
AF XY:
0.0000124
AC XY:
9
AN XY:
726750
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000900
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000756
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Charcot-Marie-Tooth disease type 4 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpAug 28, 2021This sequence change replaces arginine with proline at codon 621 of the MTMR2 protein (p.Arg621Pro). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and proline. This variant is present in population databases (rs371925152, ExAC 0.01%). This variant has not been reported in the literature in individuals affected with MTMR2-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.52
BayesDel_addAF
Uncertain
0.13
D
BayesDel_noAF
Pathogenic
0.22
CADD
Uncertain
25
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.52
D;.;.;.;T
Eigen
Uncertain
0.63
Eigen_PC
Pathogenic
0.67
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.89
D;D;.;.;D
M_CAP
Uncertain
0.12
D
MetaRNN
Uncertain
0.55
D;D;D;D;D
MetaSVM
Uncertain
0.78
D
MutationAssessor
Uncertain
2.4
M;.;.;.;.
PrimateAI
Uncertain
0.65
T
PROVEAN
Benign
-2.3
N;N;N;N;N
REVEL
Uncertain
0.56
Sift
Uncertain
0.026
D;D;D;D;D
Sift4G
Uncertain
0.052
T;T;T;T;.
Polyphen
0.92
P;.;.;.;.
Vest4
0.55
MutPred
0.30
Loss of MoRF binding (P = 0.0029);.;.;.;.;
MVP
0.97
MPC
0.92
ClinPred
0.53
D
GERP RS
6.2
Varity_R
0.60
gMVP
0.66

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.

Other links and lift over

dbSNP: rs371925152; hg19: chr11-95568524; API