rs121909096

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PS3PS4PS2PP2PP3PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.1856C>T variant in DNM2 is a missense variant predicted to cause substitution of serine by leucine at amino acid 619. This variant is absent from gnomAD v4.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.936, which is above the threshold of 0.7, evidence that correlates with impact to DNM2 function (PP3). DNM2, in which the variant was identified, is defined by the ClinGen CM VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). The variant has been reported in at least four probands with centronuclear myopathy that was confirmed by muscle biopsy, one of which was a de novo occurrence with parental relationships confirmed (PMIDs: PMIDs:17932957, 30208955, 34595679, PS4, PS2). In vitro assays demonstrate that the p.S619L variant increases GTPase activity (PMID:20700106), indicating that this variant impacts protein function. Additionally, a variant-specific zebrafish model (PMID:23338057) and a variant-specific mouse model (PMID:32809972) recapitulate patient phenotypes of motor problems, early impaired muscle function and force, and myofiber hypotrophy (PS4). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant centronuclear myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PS2, PS4, PM2_Supporting, PP2, PP3. (Congenital Myopathies VCEP specifications version 1; 8/7/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA172110/MONDO:0018947/148

Frequency

Genomes: not found (cov: 31)

Consequence

DNM2
NM_001005361.3 missense

Scores

16
2
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7U:1

Conservation

PhyloP100: 7.63
Variant links:
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 15 ACMG points.

PS2
PS3
PS4
PM2
PP2
PP3

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
DNM2NM_001005361.3 linkuse as main transcriptc.1856C>T p.Ser619Leu missense_variant 17/21 ENST00000389253.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
DNM2ENST00000389253.9 linkuse as main transcriptc.1856C>T p.Ser619Leu missense_variant 17/215 NM_001005361.3 A1P50570-4

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
Cov.:
33
GnomAD4 genome
Cov.:
31

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:7Uncertain:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Autosomal dominant centronuclear myopathy Pathogenic:2
Likely pathogenic, criteria provided, single submitterclinical testingNeuroMeGen, Hospital Clinico Santiago de CompostelaOct 08, 2018- -
Pathogenic, criteria provided, single submitterclinical testingCentogene AG - the Rare Disease Company-- -
Charcot-Marie-Tooth disease dominant intermediate B Pathogenic:1Uncertain:1
Pathogenic, criteria provided, single submitterclinical testingInvitaeOct 13, 2023This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 619 of the DNM2 protein (p.Ser619Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with centronuclear myopathy and is associated with severe neonatal hypotonia (PMID: 17932957, 20227276, 22396310). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 7285). 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. Experimental studies have shown that this missense change affects DNM2 function (PMID: 20700106, 23338057, 24135484, 26199319). This variant disrupts the p.Ser619 amino acid residue in DNM2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17932957, 20700106, 22396310, 25957634). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Uncertain significance, no assertion criteria providedliterature onlyInherited Neuropathy Consortium Ii, University Of MiamiJan 06, 2016- -
Severe X-linked myotubular myopathy Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMDec 01, 2007- -
not provided Pathogenic:1
Pathogenic, no assertion criteria providedclinical testingLaboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de NantesDec 12, 2016- -
Charcot-Marie-Tooth disease dominant intermediate B;C4551952:Autosomal dominant centronuclear myopathy;C4706410:Fetal akinesia-cerebral and retinal hemorrhage syndrome Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsAug 20, 2021- -
Centronuclear myopathy Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoFeb 08, 2013- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.55
D
BayesDel_noAF
Pathogenic
0.55
CADD
Pathogenic
33
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.93
.;.;.;D;.
Eigen
Pathogenic
0.83
Eigen_PC
Pathogenic
0.75
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Pathogenic
1.0
D;D;D;D;D
M_CAP
Pathogenic
0.41
D
MetaRNN
Pathogenic
0.98
D;D;D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.0
M;.;M;M;.
MutationTaster
Benign
1.0
D;D;D;D;D;D
PrimateAI
Pathogenic
0.86
D
PROVEAN
Pathogenic
-4.4
.;D;D;.;D
REVEL
Pathogenic
0.94
Sift
Uncertain
0.0010
.;D;D;.;D
Sift4G
Uncertain
0.015
D;D;D;D;D
Polyphen
1.0, 1.0
.;D;.;D;.
Vest4
0.89
MutPred
0.93
Gain of helix (P = 0.0225);.;Gain of helix (P = 0.0225);Gain of helix (P = 0.0225);.;
MVP
0.99
MPC
2.0
ClinPred
1.0
D
GERP RS
4.9
RBP_binding_hub_radar
0.92
RBP_regulation_power_radar
3.0
Varity_R
0.89
gMVP
0.95

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: rs121909095; hg19: chr19-10934538; COSMIC: COSV58960962; API