rs587783595

Variant names:

• chr19-10812271-G-A
• rs587783595
• NM_001005361.3:c.1565G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-10812271-G-A
• chr19-10812271-G-T

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2_Supporting PS4 PS2 PP2 PP3 PP1_Moderate PS3_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_001005361.3:c.1565G>A variant in DNM2 is a missense variant predicted to cause substitution of arginine by histidine at amino acid 522 (p.Arg522His). The variant is absent from gnomAD v4.1.0 meeting PM2_Supporting. DNM2, in which the variant was identified, is defined by the ClinGen Congenital Myopathies VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). The REVEL computational prediction analysis tool gives a score of 0.892, which is above the threshold necessary to apply PP3. This variant has been reported in at least eight probands with centronuclear myopathy, of which two were identified to be de novo occurrences (PS2, PS4; PMIDs: 20227276, 29105112, 32826616; Baylor Genetics, GeneDx, Athena Diagnostics, ClinVar: SCV000807289.2, SCV000329752.6, SCV000841851.1; VCEP Internal data contributor). Additionally, the variant segregated with disease in 4 family members meeting PP1_Moderate (PMID:20227276). Live correlative scanning ion conductance microscopy (SICM) and fluorescence confocal microscopy (FCM) showed that the p.Arg522His variant slows down the formation of clathrin-coated pits in skin fibroblasts from patients and in Cos-7 cells expressing corresponding dynamin mutants (PS3_Supporting, PMID:31017801). In summary, the variant meets the criteria to be classified as pathogenic for autosomal dominant centronuclear myopathy. ACMG/AMP criteria met, as specified by the ClinGen Congenital Myopathies VCEP: PS2, PS4, PP1_Moderate, PS3_Supporting, PM2_Supporting, PP2, PP3 (ClinGen Congenital Myopathies VCEP specifications version 1.0.0; 4/14/2025 LINK:https://erepo.genome.network/evrepo/ui/classification/CA172101/MONDO:0018947/148

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: DNM2 NM_001005361.3 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:11 U:1
• Conservation: PhyloP100: 10.0
• Publications: 29 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

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PS2: For more information check the summary or visit ClinGen Evidence Repository.
• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP2: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

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.1565G>A	p.Arg522His	missense	Exon 15 of 21	NP_001005361.1	P50570-4
	DNM2	NM_001005360.3		c.1565G>A	p.Arg522His	missense	Exon 15 of 21	NP_001005360.1	P50570-1
	DNM2	NM_001190716.2		c.1565G>A	p.Arg522His	missense	Exon 15 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.1565G>A	p.Arg522His	missense	Exon 15 of 21	ENSP00000373905.4	P50570-4
	DNM2	ENST00000355667.11	TSL:1	c.1565G>A	p.Arg522His	missense	Exon 15 of 21	ENSP00000347890.6	P50570-1
	DNM2	ENST00000585892.5	TSL:1	c.1565G>A	p.Arg522His	missense	Exon 15 of 21	ENSP00000468734.1	P50570-5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1447522 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 719044

African (AFR) AF: 0.00 AC: 0 AN: 33194

American (AMR) AF: 0.00 AC: 0 AN: 42202

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25820

East Asian (EAS) AF: 0.00 AC: 0 AN: 39140

South Asian (SAS) AF: 0.00 AC: 0 AN: 84812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51954

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1104796

Other (OTH) AF: 0.00 AC: 0 AN: 59854

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
4	-	-	not provided (4)
3	-	-	Autosomal dominant centronuclear myopathy (3)
2	-	-	Centronuclear myopathy (2)
1	1	-	Charcot-Marie-Tooth disease dominant intermediate B (2)
1	-	-	See cases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.92	D
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.44	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.56	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		10
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-4.4	D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.018	D
Polyphen		0.12	B
Vest4		0.71
MutPred		0.88		Loss of MoRF binding (P = 0.0101)
MVP		0.91
MPC		2.3
ClinPred		1.0	D
GERP RS		5.3
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.9
Varity_R		0.68
gMVP		0.91
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs587783595; hg19: chr19-10922947; COSMIC: COSV58957808;