rs121909091

Variant names:

• chr19-10798543-C-T
• rs121909091
• NM_001005361.3:c.1393C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-10798543-C-T
• chr19-10798543-C-A

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PS3 PS4 PP1_Strong PP3

This summary comes from the ClinGen Evidence Repository: The variant NM_001005361.3:c.1393C>T in DNM2 is a missense variant predicted to cause substitution of arginine by tryptophan at amino acid 465 (p.Arg465Trp). The highest population minor allele frequency in gnomAD v4.1 is 0.000001695 (2/1180018 alleles) in the European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met). The REVEL computational prediction analysis tool produced a score of 0.83, which is above the threshold necessary to apply PP3. This variant has been reported in at least six probands with confirmed centronuclear myopathy (PS4; PMID:16227997, 19130742, 22613877, 26908122, 28740838, 34463354, 34595679). In addition, it segregated in five affected individuals in one family (PP1_Strong; PMID:16227997). Functional studies have demonstrated that this variant increases GTPase activity compared to wildtype dynamin (PMIDs: 20529869, 26199319). Several knock-in mouse models with the variant have been created and show muscle defects, progressive atrophy and morphological abnormalities similar to those observed in human biopsies, and DNM2 reduction has been shown to rescue the phenotype in mice (PS3; PMIDs: 20858595, 30291191). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant centronuclear myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PP3, PS4, PP1_Strong, PS3. (ClinGen Congenital Myopathies VCEP specifications version 1; 8/7/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA172098/MONDO:0018947/148

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DNM2 NM_001005361.3 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:17 U:1
• Conservation: PhyloP100: 1.07
• Publications: 66 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 13 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: 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.1393C>T	p.Arg465Trp	missense	Exon 11 of 21	NP_001005361.1	P50570-4
	DNM2	NM_001005360.3		c.1393C>T	p.Arg465Trp	missense	Exon 11 of 21	NP_001005360.1	P50570-1
	DNM2	NM_001190716.2		c.1393C>T	p.Arg465Trp	missense	Exon 11 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.1393C>T	p.Arg465Trp	missense	Exon 11 of 21	ENSP00000373905.4	P50570-4
	DNM2	ENST00000355667.11	TSL:1	c.1393C>T	p.Arg465Trp	missense	Exon 11 of 21	ENSP00000347890.6	P50570-1
	DNM2	ENST00000585892.5	TSL:1	c.1393C>T	p.Arg465Trp	missense	Exon 11 of 21	ENSP00000468734.1	P50570-5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461872 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727240

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: 26136

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: 53420

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

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111994

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 31

Alfa AF: 0.00000494 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
6	-	-	not provided (6)
5	-	-	Autosomal dominant centronuclear myopathy (5)
3	-	-	Centronuclear myopathy (3)
1	1	-	Charcot-Marie-Tooth disease dominant intermediate B (2)
1	-	-	Abnormality of the musculature (1)
1	-	-	DNM2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.96	D
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.62	D
MutationAssessor	Pathogenic	3.6	H
PhyloP100		1.1
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-7.2	D
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.91
MutPred		0.91		Loss of disorder (P = 0.0057)
MVP		0.94
MPC		2.2
ClinPred		1.0	D
GERP RS		2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.89
gMVP		0.86
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs121909091; hg19: chr19-10909219; COSMIC: COSV58963902; COSMIC: COSV58963902;