19-10829116-T-C

Position:

• chr19-10829116-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001005361.3(DNM2):​c.2139T>C​(p.Ala713=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.307 in 1,613,602 control chromosomes in the GnomAD database, including 78,330 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A713A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.30 (7084 hom., cov: 33)
  • Exomes 𝑓: 0.31 (71246 hom.)
• Consequence: DNM2 NM_001005361.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -4.76

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 19-10829116-T-C is Benign according to our data. Variant chr19-10829116-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 158523.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-10829116-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-4.76 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.561 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNM2	NM_001005361.3	c.2139T>C	p.Ala713=	synonymous_variant	19/21	ENST00000389253.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNM2	ENST00000389253.9	c.2139T>C	p.Ala713=	synonymous_variant	19/21	5	NM_001005361.3	A1

Frequencies

GnomAD3 genomes AF: 0.300 AC: 45622 AN: 151982 Hom.: 7058 Cov.: 33

Gnomad AFR AF: 0.279

Gnomad AMI AF: 0.314

Gnomad AMR AF: 0.271

Gnomad ASJ AF: 0.310

Gnomad EAS AF: 0.578

Gnomad SAS AF: 0.303

Gnomad FIN AF: 0.342

Gnomad MID AF: 0.357

Gnomad NFE AF: 0.291

Gnomad OTH AF: 0.296

GnomAD3 exomes AF: 0.312 AC: 78204 AN: 250390 Hom.: 12924 AF XY: 0.313 AC XY: 42359 AN XY: 135494

Gnomad AFR exome AF: 0.281

Gnomad AMR exome AF: 0.256

Gnomad ASJ exome AF: 0.319

Gnomad EAS exome AF: 0.564

Gnomad SAS exome AF: 0.313

Gnomad FIN exome AF: 0.321

Gnomad NFE exome AF: 0.291

Gnomad OTH exome AF: 0.313

GnomAD4 exome AF: 0.308 AC: 449698 AN: 1461502 Hom.: 71246 Cov.: 56 AF XY: 0.307 AC XY: 223397 AN XY: 727050

Gnomad4 AFR exome AF: 0.281

Gnomad4 AMR exome AF: 0.255

Gnomad4 ASJ exome AF: 0.313

Gnomad4 EAS exome AF: 0.576

Gnomad4 SAS exome AF: 0.309

Gnomad4 FIN exome AF: 0.317

Gnomad4 NFE exome AF: 0.300

Gnomad4 OTH exome AF: 0.315

GnomAD4 genome AF: 0.300 AC: 45696 AN: 152100 Hom.: 7084 Cov.: 33 AF XY: 0.305 AC XY: 22708 AN XY: 74356

Gnomad4 AFR AF: 0.280

Gnomad4 AMR AF: 0.271

Gnomad4 ASJ AF: 0.310

Gnomad4 EAS AF: 0.578

Gnomad4 SAS AF: 0.303

Gnomad4 FIN AF: 0.342

Gnomad4 NFE AF: 0.291

Gnomad4 OTH AF: 0.297

Alfa AF: 0.286 Hom.: 9848

Bravo AF: 0.298

Asia WGS AF: 0.419 AC: 1459 AN: 3478

EpiCase AF: 0.303

EpiControl AF: 0.296

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 12, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	Ala713Ala in exon 19 of DNM2: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue and is not located with in the splice consensus sequence. It has been identified in 29.1% (2504/8600) of European American chromosomes from a broad population by the NHLBI Exome Sequen cing Project (http://evs.gs.washington.edu/EVS; dbSNP rs2229920). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

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

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -

Autosomal dominant centronuclear myopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.23
DANN	Benign	0.45
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs2229920; hg19: chr19-10939792; COSMIC: COSV53033084; COSMIC: COSV53033084;