rs121909089

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM2_SupportingPS4PP1_StrongPP2PP3PM6

This summary comes from the ClinGen Evidence Repository: The c.1106 G>A (NM_001005361.3(DNM2):c.1106G>A (p.Arg369Gln)) variant in DNM2 is a missense variant predicted to cause substitution of Arg by Gln at amino acid 369. The variant was found in at least 16 individuals from 2 families, all with centronuclear myopathy (PS4; PMIDs: 16227997, 26908122). The mutation segregated in 14 affected family members from 2 families (PP1_strong; PMIDs: 16227997, 26908122). This variant has been identified as a de novo occurrence with an unconfirmed parental relationship in 1 individual with centronuclear myopathy (PM6; PMID:16227997). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.7, (rounded from 0.698), which meets 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 Congenital Myopathies 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). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant centronuclear myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: (PS4, PP1_strong, PM6, PM2_supporting, PP3, PP2; Version 1, 8/7/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA118655/MONDO:0018947/148

Frequency

Genomes: not found (cov: 32)

Consequence

DNM2
NM_001005361.3 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:8U:1

Conservation

PhyloP100: 10.0

Publications

24 publications found

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]

DNM2 Gene-Disease associations (from GenCC):

autosomal dominant centronuclear myopathy
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: ClinGen, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
Charcot-Marie-Tooth disease
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
Charcot-Marie-Tooth disease dominant intermediate B
Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
autosomal dominant Charcot-Marie-Tooth disease type 2M
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
fetal akinesia-cerebral and retinal hemorrhage syndrome
Inheritance: AR Classification: SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
hereditary spastic paraplegia
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

DNM2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 13 ACMG points.

PS4

For more information check the summary or visit ClinGen Evidence Repository.

PM2

For more information check the summary or visit ClinGen Evidence Repository.

PM6

For more information check the summary or visit ClinGen Evidence Repository.

PP1

For more information check the summary or visit ClinGen Evidence Repository.

PP2

For more information check the summary or visit ClinGen Evidence Repository.

PP3

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNM2	NM_001005361.3 link	c.1106G>A	p.Arg369Gln	missense_variant	Exon 8 of 21	ENST00000389253.9	NP_001005361.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNM2	ENST00000389253.9 link	c.1106G>A	p.Arg369Gln	missense_variant	Exon 8 of 21	5	NM_001005361.3	ENSP00000373905.4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8Uncertain:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Charcot-Marie-Tooth disease dominant intermediate B

Pathogenic:2Uncertain:1

Nov 14, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 369 of the DNM2 protein (p.Arg369Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with centronuclear myopathy and centronuclear myopathy with and without myotonia (PMID: 16227997, 19130742, 24366529, 25501959, 26908122). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 7279). Invitae Evidence 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 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. This variant disrupts the p.Arg369 amino acid residue in DNM2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16227997, 20529869, 20817456, 22613877, 24016602, 25492887, 28676641). 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. -

Jun 10, 2022

DASA

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1106G>A;p.(Arg369Gln) missense change has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 7279; PMID: 28676641; 24366529; 25501959; 25492887; 24016602) - PS4. The variant is located in a mutational hot spot and/or critical and well-established functional domain (Dynamin_M) - PM1. This variant is not present in population databases:rs121909089, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. Pathogenic missense variant in this residue have been reported and classified as Pathogenic by ACMG criteria (Clinvar ID: 245905; 7280) - PM5. The variant co-segregated with disease in multiple affected family members (PMID: 25501959) - PP1. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is Pathogenic -

Jan 06, 2016

Inherited Neuropathy Consortium Ii, University Of Miami

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Autosomal dominant centronuclear myopathy

Pathogenic:2

Neuberg Centre For Genomic Medicine, NCGM

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The missense variant p.R369Q in DNM2 (NM_001005360.3) has been reported in individuals affected with centronuclear myopathy with and without myotonia (Bitoun M et al, 2005; Chen T et al, 2015; Lin P et al, 2016; Jeub M et al, 2012; Dabby R et al, 2014). The p.R369Q variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The p.R369Q missense variant is predicted to be damaging by both SIFT and PolyPhen2. The arginine residue at codon 369 of DNM2 is conserved in all mammalian species. The nucleotide c.1106 in DNM2 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -

Nov 01, 2005

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not provided

Pathogenic:2

Dec 17, 2024

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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: Fujise2021[article], 28971531, 22613877, 22396310, 28676641, 25492887, 26908122, 30925452, 20529869, 24366529, 16227997, 25501959, 19130742, 30149909, 31321302, 32403337, 28000226, 24465259, 32298515, 26215883, 20817456, 20227276, 21221624, 20858595, 24016602, 34426522, 34595679, 27535533) -

Aug 10, 2021

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Centronuclear myopathy

Pathogenic:2

Aug 07, 2024

ClinGen Congenital Myopathies Variant Curation Expert Panel, ClinGen

Significance:Pathogenic

Review Status:reviewed by expert panel

Collection Method:curation

The c.1106 G>A (NM_001005361.3(DNM2):c.1106G>A (p.Arg369Gln)) variant in DNM2 is a missense variant predicted to cause substitution of Arg by Gln at amino acid 369. The variant was found in at least 16 individuals from 2 families, all with centronuclear myopathy (PS4; PMIDs: 16227997, 26908122). The mutation segregated in 14 affected family members from 2 families (PP1_strong; PMIDs: 16227997, 26908122). This variant has been identified as a de novo occurrence with an unconfirmed parental relationship in 1 individual with centronuclear myopathy (PM6; PMID: 16227997). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.7, (rounded from 0.698), which meets 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 Congenital Myopathies 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). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant centronuclear myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: (PS4, PP1_strong, PM6, PM2_supporting, PP3, PP2; Version 1, 8/7/2024). -

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.83

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.30

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.89

.;.;.;D;.;D

Eigen

Pathogenic

0.72

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.96

D;D;D;D;D;D

M_CAP

Uncertain

0.11

MetaRNN

Pathogenic

0.97

D;D;D;D;D;D

MetaSVM

Uncertain

0.060

MutationAssessor

Uncertain

2.8

M;M;M;M;M;.

PhyloP100

PrimateAI

Pathogenic

0.86

PROVEAN

Uncertain

-3.7

.;D;D;D;D;.

REVEL

Pathogenic

0.70

Sift

Uncertain

0.028

.;D;D;D;D;.

Sift4G

Benign

0.063

T;T;T;T;T;D

Polyphen

0.98, 0.80

.;D;.;P;.;.

Vest4

0.88

MutPred

0.92

Loss of methylation at R369 (P = 0.0439);Loss of methylation at R369 (P = 0.0439);Loss of methylation at R369 (P = 0.0439);Loss of methylation at R369 (P = 0.0439);Loss of methylation at R369 (P = 0.0439);.;

MVP

0.95

MPC

2.3

ClinPred

0.97

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.78

gMVP

0.83

Mutation Taster

=1/99

disease causing (ClinVar)

(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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over