rs587783595

Positions:

• chr19-10812271-G-A
• chr19-10812271-G-T

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R522C) has been classified 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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9 U:1
• 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]

ACMG classification

Verdict is Pathogenic. Variant got 19 ACMG points.

• PM1: In a strand (size 8) in uniprot entity DYN2_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) 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 chr19-10812270-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 986927.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant where missense usually causes diseases, DNM2
• 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	UniProt
DNM2	NM_001005361.3	c.1565G>A	p.Arg522His	missense_variant	15/21	ENST00000389253.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNM2	ENST00000389253.9	c.1565G>A	p.Arg522His	missense_variant	15/21	5	NM_001005361.3	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1447522 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 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.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

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	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	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2018	- -

Autosomal dominant centronuclear myopathy Pathogenic:2

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. -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	May 19, 2022	- -

Charcot-Marie-Tooth disease dominant intermediate B Pathogenic:1 Uncertain: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	Invitae	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	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	29
DANN	Pathogenic	1.0
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D
M_CAP	Pathogenic	0.44	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D
MetaSVM	Uncertain	0.56	D
MutationAssessor	Uncertain	2.3	M;.;M;M;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.79	T
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	D
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

Other links and lift over

dbSNP: rs587783595; hg19: chr19-10922947; COSMIC: COSV58957808;