rs587783595

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PP2PP3_StrongPP5_Very_Strong

The NM_001005361.3(DNM2):c.1565G>A(p.Arg522His) 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. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

DNM2
NM_001005361.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9U:1

Conservation

PhyloP100: 10.0

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 17 ACMG points.

PM1

In a domain PH (size 106) in uniprot entity DYN2_HUMAN there are 17 pathogenic changes around while only 0 benign (100%) in NM_001005361.3

PM2

Very rare variant in population databases, with high coverage;

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, 0.968

PP5

Variant 19-10812271-G-A is Pathogenic according to our data. Variant chr19-10812271-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 158514.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-10812271-G-A is described in Lovd as [Likely_pathogenic]. Variant chr19-10812271-G-A is described in Lovd as [Pathogenic]. Variant chr19-10812271-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNM2	NM_001005361.3 linkuse as main transcript	c.1565G>A	p.Arg522His	missense_variant	15/21	ENST00000389253.9	NP_001005361.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNM2	ENST00000389253.9 linkuse as main transcript	c.1565G>A	p.Arg522His	missense_variant	15/21	5	NM_001005361.3	ENSP00000373905	A1	P50570-4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1447522

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

719044

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 26, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 04, 2019	Reported in association with centronuclear myopathy in published literature (Susman et al., 2010; Chen et al., 2015); Published functional studies demonstrate that R522H impairs protein interaction with microtubules and results in reduced clathrin-mediated endocytosis (Koutsopoulos et al., 2011; Bragato et al., 2016); Not observed in large population cohorts (Lek et al., 2016); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; A diffferent missense change at this residue (R522C) has been reported in the Human Gene Mutation Database in association with CNM (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 26908122, 22096584, 26842864, 20227276, 25501959, 27363342, 29105112, 28357410, 31017801, 32826616) -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 07, 2017	- -

Autosomal dominant centronuclear myopathy

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	May 19, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 01, 2017	This mutation has been previously reported as disease-causing and was found once in our laboratory de novo in a 16-year-old female with centronuclear myopathy on muscle biopsy; proximal muscle weakness, facial weakness, fatigue, varus foot, waddling gait. -

Charcot-Marie-Tooth disease dominant intermediate B

Pathogenic:1Uncertain:1

Uncertain significance, no assertion criteria provided	literature only	Inherited Neuropathy Consortium Ii, University Of Miami	Jan 06, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 01, 2023	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 522 of the DNM2 protein (p.Arg522His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with centronuclear myopathy (PMID: 20227276, 22396310, 24465259, 25501959, 25957634, 26908122). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 158514). 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: 22096584, 26842864). For these reasons, this variant has been classified as Pathogenic. -

See cases

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Aug 20, 2020

ACMG classification criteria: PS4, PM2, PM6, PP1 -

Centronuclear myopathy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 08, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.91

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.33

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.92

.;.;.;D;.;T

Eigen

Pathogenic

0.76

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

D;D;D;D;D;D

M_CAP

Pathogenic

0.44

MetaRNN

Pathogenic

0.97

D;D;D;D;D;D

MetaSVM

Uncertain

0.56

MutationAssessor

Uncertain

2.3

M;.;M;M;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D

PrimateAI

Uncertain

0.79

PROVEAN

Pathogenic

-4.4

.;.;D;.;D;.

REVEL

Pathogenic

0.89

Sift

Uncertain

0.0010

.;.;D;.;D;.

Sift4G

Uncertain

0.018

D;D;D;D;D;D

Polyphen

0.12, 1.0

.;B;.;D;.;.

Vest4

0.71

MutPred

0.88

Loss of MoRF binding (P = 0.0101);.;Loss of MoRF binding (P = 0.0101);Loss of MoRF binding (P = 0.0101);.;.;

MVP

0.91

MPC

2.3

ClinPred

1.0

GERP RS

5.3

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.9

Varity_R

0.68

gMVP

0.91

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over