rs121909093

Positions:

• chr19-10812315-G-A
• chr19-10812315-G-T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_001005361.3(DNM2):​c.1609G>A​(p.Gly537Ser) 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. G537C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DNM2 NM_001005361.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• 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 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-10812315-G-T is described in Lovd as [Pathogenic].
• 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, 0.853
• PP5: Variant 19-10812315-G-A is Pathogenic according to our data. Variant chr19-10812315-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 246295.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNM2	NM_001005361.3	c.1609G>A	p.Gly537Ser	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	c.1609G>A	p.Gly537Ser	missense_variant	15/21	5	NM_001005361.3	ENSP00000373905	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 21, 2022	Identified in a siblings with progressive weakness, muscular atrophy, and a clinical diagnosis of Charcot-Marie-Tooth neuropathy inherited from their affected mother in the published literature (San Luis et al., 2022); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27698851, 16227997, 30373780, 35993408) -

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 02, 2023

The c.1609G>A (p.G537S) alteration is located in exon 15 (coding exon 15) of the DNM2 gene. This alteration results from a G to A substitution at nucleotide position 1609, causing the glycine (G) at amino acid position 537 to be replaced by a serine (S)._x000D_ _x000D_ Based on the available evidence, the DNM2 c.1609G>A (p.G537S) alteration is classified as likely pathogenic for DNM2-related Charcot-Marie-Tooth disease; however, its clinical significance for DNM2-related centronuclear myopathy is unclear. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been reported in the heterozygous state in multiple individuals with features consistent with DNM2-related Charcot-Marie-Tooth disease (San Luis, 2022; Bacquet, 2018; Ambry internal data). In addition, this alteration has been reported as de novo in one individual with a clinical diagnosis of Charcot-Marie-Tooth disease (external communication). This amino acid position is highly conserved in available vertebrate species. The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as likely pathogenic. -

Charcot-Marie-Tooth disease dominant intermediate B Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 29, 2020

Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly537 amino acid residue in DNM2. Other variant(s) that disrupt this residue have been observed in individuals with DNM2-related conditions (PMID: 17636067), which suggests that this may be a clinically significant amino acid residue. This variant has been observed in individual(s) with Charcot-Marie-Tooth disease (PMID: 30373780, Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 246295). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with serine at codon 537 of the DNM2 protein (p.Gly537Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. -

Sensorimotor neuropathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Aug 05, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	.;.;.;D;.
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.85	D;D;D;D;D
MetaSVM	Uncertain	0.28	D
MutationAssessor	Uncertain	2.4	M;.;M;M;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-3.9	.;.;D;.;D
REVEL	Pathogenic	0.65
Sift	Benign	0.067	.;.;T;.;D
Sift4G	Benign	0.067	T;D;T;T;D
Polyphen		0.98, 0.94	.;D;.;P;.
Vest4		0.75
MutPred		0.65		Gain of catalytic residue at M534 (P = 0.0394);.;Gain of catalytic residue at M534 (P = 0.0394);Gain of catalytic residue at M534 (P = 0.0394);.;
MVP		0.83
MPC		1.6
ClinPred		0.99	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.47
gMVP		0.92

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

Other links and lift over

dbSNP: rs121909093; hg19: chr19-10922991; COSMIC: COSV99042600; COSMIC: COSV99042600;