rs142155860

Variant summary

Our verdict is Benign. Variant got -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

2
10
6

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 7.16
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 Benign. Variant got -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 id is 306544.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}.
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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 17 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MTMR2NM_016156.6 linkuse as main transcriptc.547G>T p.Ala183Ser missense_variant 6/15 ENST00000346299.10 NP_057240.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MTMR2ENST00000346299.10 linkuse as main transcriptc.547G>T p.Ala183Ser missense_variant 6/151 NM_016156.6 ENSP00000345752 P3Q13614-1

Frequencies

GnomAD3 genomes
AF:
0.00457
AC:
695
AN:
152144
Hom.:
17
Cov.:
32
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
GnomAD3 exomes
AF:
0.00474
AC:
1190
AN:
251052
Hom.:
27
AF XY:
0.00455
AC XY:
617
AN XY:
135696
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 SAS 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.:
56
Cov.:
29
AF XY:
0.00184
AC XY:
1333
AN XY:
725978
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0458
Gnomad4 NFE exome
AF:
0.000232
Gnomad4 OTH exome
AF:
0.00153
GnomAD4 genome
AF:
0.00456
AC:
695
AN:
152262
Hom.:
17
Cov.:
32
AF XY:
0.00712
AC XY:
530
AN XY:
74454
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.0594
Gnomad4 NFE
AF:
0.000926
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.000466
Hom.:
1
Bravo
AF:
0.000144
ExAC
AF:
0.00404
AC:
491
EpiCase
AF:
0.000218
EpiControl
AF:
0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Charcot-Marie-Tooth disease type 4B1 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Charcot-Marie-Tooth disease type 4 Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 22, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.19
BayesDel_addAF
Benign
-0.19
T
BayesDel_noAF
Uncertain
-0.050
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.64
D;.;.;.;T
Eigen
Uncertain
0.51
Eigen_PC
Uncertain
0.58
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.98
D;D;.;.;D
MetaRNN
Benign
0.0096
T;T;T;T;T
MetaSVM
Uncertain
-0.19
T
MutationAssessor
Uncertain
2.4
M;.;.;.;.
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Uncertain
0.78
T
PROVEAN
Uncertain
-2.6
D;D;D;D;D
REVEL
Uncertain
0.47
Sift
Benign
0.091
T;T;T;T;T
Sift4G
Benign
0.14
T;T;T;T;.
Polyphen
0.61
P;.;.;.;.
Vest4
0.58
MVP
0.83
MPC
0.50
ClinPred
0.089
T
GERP RS
5.5
Varity_R
0.56
gMVP
0.78

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs142155860; hg19: chr11-95591718; API