rs121909092

Variant names:

• chr19-10793829-G-A
• rs121909092
• NM_001005361.3:c.1102G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-10793829-G-A
• chr19-10793829-G-C

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PS3_Moderate PM2_Supporting PS4 PP2 PP3 PS2

This summary comes from the ClinGen Evidence Repository: The NM_001005361.3:c.1102G>A variant in DNM2 is a missense variant predicted to cause substitution of glutamic acid by lysine at amino acid 368 (p.Glu368Lys). This variant is absent from gnomAD v4.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.799, which is above the threshold of 0.7, evidence that correlates with impact to DNM2 function (PP3). 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). This variant has been reported in at least 6 probands with centronuclear myopathy (PS4; PMIDs: 16227997, 22613877, 25501959, 27159402, 33124102). Of those 6 individuals, the variant was identified as a de novo occurrence with confirmed parental relationships in at least 3 of those individuals with centronuclear myopathy (PS2_VeryStrong; PMIDs: 16227997, 27159402, 33124102). Oligomerization in Sf9 cells showed defective autoinhibition of self-assembly, indicating that this variant impacts protein function (PMID:26199319). Additionally, GTPase activity in Sf9 cells was between 2–2.5-fold higher than wild-type DNM2 (PS3_Moderate). 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: PS2_VeryStrong, PS4, PS3_Moderate, PM2_Supporting, PP2, PP3. (ClinGen Congenital Myopathies VCEP Specifications Version 1.0; 10/25/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA118661/MONDO:0018947/148

• Frequency: Genomes: not found (cov: 32)
• Consequence: DNM2 NM_001005361.3 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:13 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 13 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.
• 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.1102G>A	p.Glu368Lys	missense	Exon 8 of 21	NP_001005361.1	P50570-4
	DNM2	NM_001005360.3		c.1102G>A	p.Glu368Lys	missense	Exon 8 of 21	NP_001005360.1	P50570-1
	DNM2	NM_001190716.2		c.1102G>A	p.Glu368Lys	missense	Exon 8 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.1102G>A	p.Glu368Lys	missense	Exon 8 of 21	ENSP00000373905.4	P50570-4
	DNM2	ENST00000355667.11	TSL:1	c.1102G>A	p.Glu368Lys	missense	Exon 8 of 21	ENSP00000347890.6	P50570-1
	DNM2	ENST00000585892.5	TSL:1	c.1102G>A	p.Glu368Lys	missense	Exon 8 of 21	ENSP00000468734.1	P50570-5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 251474 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00000999 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
4	-	-	Autosomal dominant centronuclear myopathy (4)
2	1	-	Charcot-Marie-Tooth disease dominant intermediate B (3)
3	-	-	not provided (3)
2	-	-	Centronuclear myopathy (2)
1	-	-	DNM2-related disorder (1)
1	-	-	Myopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.90	D
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	0.45	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		10
PrimateAI	Pathogenic	0.94	D
PROVEAN	Uncertain	-3.6	D
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0080	D
Polyphen		0.17	B
Vest4		0.96
MutPred		0.89		Gain of MoRF binding (P = 0.0056)
MVP		0.96
MPC		2.0
ClinPred		0.99	D
GERP RS		4.9
Varity_R		0.90
gMVP		0.85
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: rs121909092; hg19: chr19-10904505;