19-10718279-G-C

Variant names:

• chr19-10718279-G-C
• NM_001005361.3:c.37G>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001005361.3(DNM2):​c.37G>C​(p.Val13Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: DNM2 NM_001005361.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.25

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the DNM2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 30 curated pathogenic missense variants (we use a threshold of 10). The gene has 14 curated benign missense variants. Gene score misZ: 3.4829 (above the threshold of 3.09). Trascript score misZ: 4.8575 (above the threshold of 3.09). GenCC associations: The gene is linked to 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNM2	NM_001005361.3	c.37G>C	p.Val13Leu	missense_variant	Exon 1 of 21	ENST00000389253.9	NP_001005361.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNM2	ENST00000389253.9	c.37G>C	p.Val13Leu	missense_variant	Exon 1 of 21	5	NM_001005361.3	ENSP00000373905.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal dominant centronuclear myopathy Uncertain:1

Sep 19, 2023

Department of Pathophysiology and Transplantation, University of Milan

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

i) the variant is absent from population database (GnomAD MAF:0); ii) the variant was not present in patient’s parents, confirming de novo inheritance (previously observed for several other pathogenic DNM2 variants) and excluding the chance of a rare (private) inherited polymorphism; iii) the affected position is highly conserved across species and among DNM2 homolog genes DNM1 and DNM3; iv) several pathogenicity prediction tools support (or does not exclude) the pathogenic role of this missense variant; v) the rate of benign missense DNM2 mutations is low; vi) histological analysis in patient's muscle detects the presence of centralized nuclei and fiber size variation / hypotrophy. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.62	.;.;.;D;.
Eigen	Benign	0.14
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D;D;D;D;D
M_CAP	Pathogenic	0.84	D
MetaRNN	Uncertain	0.61	D;D;D;D;D
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Pathogenic	3.0	M;M;M;M;M
PrimateAI	Pathogenic	0.80	D
PROVEAN	Benign	-2.1	.;N;N;N;N
REVEL	Pathogenic	0.68
Sift	Uncertain	0.0020	.;D;D;D;D
Sift4G	Uncertain	0.0050	D;D;D;D;D
Polyphen		0.34, 0.26	.;B;.;B;.
Vest4		0.35
MutPred		0.61		Loss of ubiquitination at K15 (P = 0.1381);Loss of ubiquitination at K15 (P = 0.1381);Loss of ubiquitination at K15 (P = 0.1381);Loss of ubiquitination at K15 (P = 0.1381);Loss of ubiquitination at K15 (P = 0.1381);
MVP		0.88
MPC		1.1
ClinPred		0.98	D
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.61
gMVP		0.63

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-10828955;