rs121909088

Positions:

• chr19-10819992-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP2 PP3_Moderate

The NM_001005361.3(DNM2):​c.1684A>G​(p.Lys562Glu) 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 Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DNM2 NM_001005361.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity no assertion criteria provided P:1 U:2
• Conservation: PhyloP100: 9.23

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 Likely_pathogenic. Variant got 7 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, 0.924

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNM2	NM_001005361.3	c.1684A>G	p.Lys562Glu	missense_variant	16/21	ENST00000389253.9	NP_001005361.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNM2	ENST00000389253.9	c.1684A>G	p.Lys562Glu	missense_variant	16/21	5	NM_001005361.3	ENSP00000373905	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2

Revision: no assertion criteria provided

Submissions by phenotype

Charcot-Marie-Tooth disease, dominant intermediate B, with neutropenia Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 01, 2005

- -

Charcot-Marie-Tooth disease Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Inherited Neuropathy Consortium

-

- -

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

Uncertain significance, no assertion criteria provided

literature only

Inherited Neuropathy Consortium Ii, University Of Miami

Jan 06, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	.;.;.;D;.
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D
MetaSVM	Uncertain	0.27	D
MutationAssessor	Pathogenic	3.0	M;.;M;M;.
MutationTaster	Benign	1.0	A;A;A;A;A;A
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-3.4	.;.;D;.;D
REVEL	Pathogenic	0.79
Sift	Benign	0.034	.;.;D;.;D
Sift4G	Uncertain	0.035	D;D;D;D;D
Polyphen		0.11, 0.14	.;B;.;B;.
Vest4		0.79
MutPred		0.83		Loss of ubiquitination at K562 (P = 0.027);.;Loss of ubiquitination at K562 (P = 0.027);Loss of ubiquitination at K562 (P = 0.027);.;
MVP		0.96
MPC		2.1
ClinPred		0.99	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		3.8
Varity_R		0.65
gMVP		0.98

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: rs121909088; hg19: chr19-10930668;