19-10823862-C-T

Position:

• chr19-10823862-C-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.1856C>T​(p.Ser619Leu) 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. 13/21 in silico tools predict a damaging 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. S619W) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: DNM2 NM_001005361.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7 U:1
• Conservation: PhyloP100: 7.63

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 hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 5 uncertain 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 chr19-10823862-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 7286.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant where missense usually causes diseases, DNM2
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985
• PP5: Variant 19-10823862-C-T is Pathogenic according to our data. Variant chr19-10823862-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 7285.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-10823862-C-T is described in Lovd as [Likely_pathogenic]. Variant chr19-10823862-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNM2	NM_001005361.3	c.1856C>T	p.Ser619Leu	missense_variant	17/21	ENST00000389253.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNM2	ENST00000389253.9	c.1856C>T	p.Ser619Leu	missense_variant	17/21	5	NM_001005361.3	A1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal dominant centronuclear myopathy Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	NeuroMeGen, Hospital Clinico Santiago de Compostela	Oct 08, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	-	- -

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

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 13, 2023	This 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 provided	literature only	Inherited Neuropathy Consortium Ii, University Of Miami	Jan 06, 2016	- -

Severe X-linked myotubular myopathy Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 01, 2007

- -

not provided Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes

Dec 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 submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 20, 2021

- -

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	0.99
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	33
DANN	Pathogenic	1.0
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
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

Other links and lift over

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