rs121909092
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_001005361.3(DNM2):c.1102G>A(p.Glu368Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E368Q) has been classified as Uncertain significance.
Frequency
Genomes: not found (cov: 32)
Consequence
DNM2
NM_001005361.3 missense
NM_001005361.3 missense
Scores
14
4
1
Clinical Significance
Conservation
PhyloP100: 10.0
Genes affected
DNM2 (HGNC:2974): (dynamin 2) Dynamins represent one of the subfamilies of GTP-binding proteins. These proteins share considerable sequence similarity over the N-terminal portion of the molecule, which contains the GTPase domain. Dynamins are associated with microtubules. They have been implicated in cell processes such as endocytosis and cell motility, and in alterations of the membrane that accompany certain activities such as bone resorption by osteoclasts. Dynamins bind many proteins that bind actin and other cytoskeletal proteins. Dynamins can also self-assemble, a process that stimulates GTPase activity. Five alternatively spliced transcripts encoding different proteins have been described. Additional alternatively spliced transcripts may exist, but their full-length nature has not been determined. [provided by RefSeq, Jun 2010]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 19 ACMG points.
PM1
In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_001005361.3
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), DNM2. . Gene score misZ 3.4829 (greater than the threshold 3.09). Trascript score misZ 4.8575 (greater than threshold 3.09). GenCC has associacion of gene with fetal akinesia-cerebral and retinal hemorrhage syndrome, Charcot-Marie-Tooth disease dominant intermediate B, hereditary spastic paraplegia, Charcot-Marie-Tooth disease, autosomal dominant centronuclear myopathy, autosomal dominant Charcot-Marie-Tooth disease type 2M.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.964
PP5
Variant 19-10793829-G-A is Pathogenic according to our data. Variant chr19-10793829-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 7282.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-10793829-G-A is described in Lovd as [Pathogenic]. Variant chr19-10793829-G-A is described in Lovd as [Likely_pathogenic]. Variant chr19-10793829-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| DNM2 | NM_001005361.3 | c.1102G>A | p.Glu368Lys | missense_variant | 8/21 | ENST00000389253.9 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| DNM2 | ENST00000389253.9 | c.1102G>A | p.Glu368Lys | missense_variant | 8/21 | 5 | NM_001005361.3 | A1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
GnomAD4 genome
Cov.:
32
ExAC
AF:
AC:
1
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:12Uncertain:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Autosomal dominant centronuclear myopathy Pathogenic:4
| Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 01, 2006 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München | Jul 06, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Breakthrough Genomics, Breakthrough Genomics | Jul 12, 2021 | This variant was previously reported in individuals affected with autosomal dominant centronuclear myopathy and considered one of the most common mutations causing the disorder and has been shown to arise de novo in numerous affected individuals [PMID: 22613877, 25501959, 25262827, 20927630, 22396310, 23338057, 20227276, 25957634, 26273216, 21221624, 23394783 16227997]. Functional studies have shown that it causes an increase in GTPase activity of the protein along and formation of oligomers that are resistant to disassembly and have a dominant negative effect on protein function [PMID: 20529869, 26199319, 21762456]. - |
| Pathogenic, criteria provided, single submitter | clinical testing | 3billion | - | The variant is not observed in the gnomAD v2.1.1 dataset. The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.80; 3Cnet: 0.97). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000007282 / PMID: 16227997 / 3billion dataset). The variant has been previously reported as assumed (i.e. paternity and maternity not confirmed) de novo in at least one similarly affected unrelated individual (PMID: 25501959, 26273216). A different missense change at the same codon (p.Glu368Gln) has been reported to be associated with DNM2 related disorder (PMID: 17825552). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. - |
not provided Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | May 12, 2016 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 14, 2022 | Published functional studies demonstrate that p.(E368K) results in increased GTPase activity, which stabilizes the dynamin complex, rendering it resistant to normal disassembly (Wang et al., 2010; Chin et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25501959, 32403337, 21221624, 26199319, 20227276, 20529869, 17008356, 21762456, 25262827, 23338057, 23394783, 26273216, 25127990, 24465259, 22613877, 33124102, 19130742, 33333461, 34463354, 22396310, 16227997) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Dec 28, 2023 | - - |
Charcot-Marie-Tooth disease dominant intermediate B Pathogenic:2Uncertain:1
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 02, 2023 | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects DNM2 function (PMID: 20529869, 21762456, 26199319). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on DNM2 protein function. ClinVar contains an entry for this variant (Variation ID: 7282). This missense change has been observed in individual(s) with autosomal dominant centronuclear myopathy (PMID: 16227997, 17008356, 19130742, 20227276, 20927630, 21221624, 22396310, 22613877, 23338057, 23394783, 24465259, 25262827, 25501959, 25957634, 26273216). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 368 of the DNM2 protein (p.Glu368Lys). - |
| Likely pathogenic, no assertion criteria provided | provider interpretation | Solve-RD Consortium | Jun 01, 2022 | Variant confirmed as disease-causing by referring clinical team - |
| Uncertain significance, no assertion criteria provided | literature only | Inherited Neuropathy Consortium Ii, University Of Miami | Jan 06, 2016 | - - |
Centronuclear myopathy Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Feb 08, 2013 | - - |
Myopathy Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Jan 01, 2017 | - - |
DNM2-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 25, 2024 | The DNM2 c.1102G>A variant is predicted to result in the amino acid substitution p.Glu368Lys. This variant has been reported in many unrelated individuals with autosomal dominant centronuclear myopathy (see example: Bitoun et al. 2005. PMID: 16227997; Mori-Yoshimura et al. 2012. PubMed ID: 22613877; Reumers. 2021. PubMed ID: 34463354). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
.;.;.;D;.;D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
M;M;M;M;M;.
MutationTaster
Benign
A;A;A;A;A;A
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
.;D;D;D;D;.
REVEL
Pathogenic
Sift
Uncertain
.;D;D;D;D;.
Sift4G
Uncertain
D;D;D;D;D;D
Polyphen
0.17, 0.40
.;B;.;B;.;.
Vest4
MutPred
Gain of MoRF binding (P = 0.0056);Gain of MoRF binding (P = 0.0056);Gain of MoRF binding (P = 0.0056);Gain of MoRF binding (P = 0.0056);Gain of MoRF binding (P = 0.0056);.;
MVP
MPC
2.0
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at