19-10793804-C-T

Variant names:

• chr19-10793804-C-T
• rs112238216
• NM_001005361.3:c.1077C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001005361.3(DNM2):​c.1077C>T​(p.Gly359Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0185 in 1,614,076 control chromosomes in the GnomAD database, including 391 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.024 (78 hom., cov: 32)
  • Exomes 𝑓: 0.018 (313 hom.)
• Consequence: DNM2 NM_001005361.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -2.69
• Publications: 5 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: ClinGen, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
• hereditary spastic paraplegia

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.24).
• BP6: Variant 19-10793804-C-T is Benign according to our data. Variant chr19-10793804-C-T is described in ClinVar as Benign. ClinVar VariationId is 137131.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.69 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0237 (3601/152186) while in subpopulation AFR AF = 0.0439 (1824/41504). AF 95% confidence interval is 0.0423. There are 78 homozygotes in GnomAd4. There are 1713 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 78 AD,AR gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNM2	NM_001005361.3	MANE Select	c.1077C>T	p.Gly359Gly	synonymous	Exon 8 of 21	NP_001005361.1
	DNM2	NM_001005360.3		c.1077C>T	p.Gly359Gly	synonymous	Exon 8 of 21	NP_001005360.1
	DNM2	NM_001190716.2		c.1077C>T	p.Gly359Gly	synonymous	Exon 8 of 21	NP_001177645.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNM2	ENST00000389253.9	TSL:5 MANE Select	c.1077C>T	p.Gly359Gly	synonymous	Exon 8 of 21	ENSP00000373905.4
	DNM2	ENST00000355667.11	TSL:1	c.1077C>T	p.Gly359Gly	synonymous	Exon 8 of 21	ENSP00000347890.6
	DNM2	ENST00000585892.5	TSL:1	c.1077C>T	p.Gly359Gly	synonymous	Exon 8 of 21	ENSP00000468734.1

Frequencies

GnomAD3 genomes AF: 0.0235 AC: 3581 AN: 152068 Hom.: 74 Cov.: 32

Gnomad AFR AF: 0.0436

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.00760

Gnomad ASJ AF: 0.0156

Gnomad EAS AF: 0.000580

Gnomad SAS AF: 0.0232

Gnomad FIN AF: 0.0205

Gnomad MID AF: 0.0191

Gnomad NFE AF: 0.0180

Gnomad OTH AF: 0.0191

GnomAD2 exomes AF: 0.0187 AC: 4706 AN: 251480 AF XY: 0.0188

Gnomad AFR exome AF: 0.0428

Gnomad AMR exome AF: 0.00778

Gnomad ASJ exome AF: 0.0159

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0249

Gnomad NFE exome AF: 0.0188

Gnomad OTH exome AF: 0.0163

GnomAD4 exome AF: 0.0180 AC: 26314 AN: 1461890 Hom.: 313 Cov.: 32 AF XY: 0.0181 AC XY: 13154 AN XY: 727246

African (AFR) AF: 0.0426 AC: 1426 AN: 33480

American (AMR) AF: 0.00803 AC: 359 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0159 AC: 415 AN: 26136

East Asian (EAS) AF: 0.000277 AC: 11 AN: 39700

South Asian (SAS) AF: 0.0253 AC: 2183 AN: 86258

European-Finnish (FIN) AF: 0.0253 AC: 1351 AN: 53420

Middle Eastern (MID) AF: 0.0194 AC: 112 AN: 5768

European-Non Finnish (NFE) AF: 0.0175 AC: 19436 AN: 1112008

Other (OTH) AF: 0.0169 AC: 1021 AN: 60396

GnomAD4 genome AF: 0.0237 AC: 3601 AN: 152186 Hom.: 78 Cov.: 32 AF XY: 0.0230 AC XY: 1713 AN XY: 74422

African (AFR) AF: 0.0439 AC: 1824 AN: 41504

American (AMR) AF: 0.00759 AC: 116 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0156 AC: 54 AN: 3468

East Asian (EAS) AF: 0.000581 AC: 3 AN: 5164

South Asian (SAS) AF: 0.0233 AC: 112 AN: 4816

European-Finnish (FIN) AF: 0.0205 AC: 218 AN: 10610

Middle Eastern (MID) AF: 0.0171 AC: 5 AN: 292

European-Non Finnish (NFE) AF: 0.0180 AC: 1223 AN: 68012

Other (OTH) AF: 0.0189 AC: 40 AN: 2116

Alfa AF: 0.0207 Hom.: 30

Bravo AF: 0.0227

Asia WGS AF: 0.0120 AC: 40 AN: 3478

EpiCase AF: 0.0185

EpiControl AF: 0.0165

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 20, 2014

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Apr 10, 2013

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Charcot-Marie-Tooth disease dominant intermediate B Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:2

Nov 26, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Autosomal dominant centronuclear myopathy Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.24
CADD	Benign	9.5
DANN	Benign	0.67
PhyloP100		-2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=89/11	polymorphism (auto)

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: rs112238216; hg19: chr19-10904480;