rs1555715216

Variant names:

• chr19-10820026-G-A
• rs1555715216
• NM_001005361.3:c.1718G>A

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_001005361.3(DNM2):​c.1718G>A​(p.Arg573His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R573C) has been classified as Uncertain significance. The gene DNM2 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DNM2 NM_001005361.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.90
• Publications: 0 publications found

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]

DNM2 Gene-Disease associations (from GenCC):

• autosomal dominant centronuclear myopathy

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, Orphanet
• Charcot-Marie-Tooth disease

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• Charcot-Marie-Tooth disease dominant intermediate B

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
• autosomal dominant Charcot-Marie-Tooth disease type 2M

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• fetal akinesia-cerebral and retinal hemorrhage syndrome

  Inheritance: AR Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• hereditary spastic paraplegia

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Specifications for DNM2 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_001005361.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.804

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001005361.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNM2	NM_001005361.3	MANE Select	c.1718G>A	p.Arg573His	missense	Exon 16 of 21	NP_001005361.1	P50570-4
	DNM2	NM_001005360.3		c.1718G>A	p.Arg573His	missense	Exon 16 of 21	NP_001005360.1	P50570-1
	DNM2	NM_001190716.2		c.1718G>A	p.Arg573His	missense	Exon 16 of 21	NP_001177645.1	P50570-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNM2	ENST00000389253.9	TSL:5 MANE Select	c.1718G>A	p.Arg573His	missense	Exon 16 of 21	ENSP00000373905.4	P50570-4
	DNM2	ENST00000355667.11	TSL:1	c.1718G>A	p.Arg573His	missense	Exon 16 of 21	ENSP00000347890.6	P50570-1
	DNM2	ENST00000585892.5	TSL:1	c.1718G>A	p.Arg573His	missense	Exon 16 of 21	ENSP00000468734.1	P50570-5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461878 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727242

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112008

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Charcot-Marie-Tooth disease dominant intermediate B (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.92	D
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Uncertain	0.57	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		9.9
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-4.3	D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.99	D
Vest4		0.73
MutPred		0.61		Gain of ubiquitination at K571 (P = 0.043)
MVP		0.92
MPC		2.3
ClinPred		0.99	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.56
gMVP		0.84
Mutation Taster		=6/94	disease causing

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

Other links and lift over

dbSNP: rs1555715216; hg19: chr19-10930702; COSMIC: COSV108121832; COSMIC: COSV108121832;