rs201979143

chr19-10830385-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001005361.3(DNM2):c.2543+7C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00475 in 1,606,916 control chromosomes in the GnomAD database, including 36 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0035 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0049 (35 hom.)
• Consequence: DNM2 NM_001005361.3 splice_region, intron
• Scores: Splicing: ADA: 0.00004586
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -1.95

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 19-10830385-C-G is Benign according to our data. Variant chr19-10830385-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 158527.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-10830385-C-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00346 (527/152276) while in subpopulation NFE AF= 0.00497 (338/68006). AF 95% confidence interval is 0.00453. There are 1 homozygotes in gnomad4. There are 269 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNM2	NM_001005361.3	c.2543+7C>G		splice_region_variant, intron_variant		ENST00000389253.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNM2	ENST00000389253.9	c.2543+7C>G		splice_region_variant, intron_variant		5	NM_001005361.3	A1

Frequencies

GnomAD3 genomes AF: 0.00346 AC: 527 AN: 152158 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000917

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00412

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00565

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00497

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00361 AC: 877 AN: 243226 Hom.: 4 AF XY: 0.00364 AC XY: 483 AN XY: 132544

Gnomad AFR exome AF: 0.00114

Gnomad AMR exome AF: 0.00354

Gnomad ASJ exome AF: 0.00696

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000360

Gnomad FIN exome AF: 0.00452

Gnomad NFE exome AF: 0.00493

Gnomad OTH exome AF: 0.00531

GnomAD4 exome AF: 0.00489 AC: 7112 AN: 1454640 Hom.: 35 Cov.: 32 AF XY: 0.00474 AC XY: 3433 AN XY: 723916

Gnomad4 AFR exome AF: 0.000956

Gnomad4 AMR exome AF: 0.00347

Gnomad4 ASJ exome AF: 0.00587

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000661

Gnomad4 FIN exome AF: 0.00471

Gnomad4 NFE exome AF: 0.00558

Gnomad4 OTH exome AF: 0.00488

GnomAD4 genome AF: 0.00346 AC: 527 AN: 152276 Hom.: 1 Cov.: 32 AF XY: 0.00361 AC XY: 269 AN XY: 74452

Gnomad4 AFR AF: 0.000914

Gnomad4 AMR AF: 0.00412

Gnomad4 ASJ AF: 0.00490

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00565

Gnomad4 NFE AF: 0.00497

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00492 Hom.: 0

Bravo AF: 0.00339

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00523

EpiControl AF: 0.00380

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:6

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 26, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 25, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	DNM2: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 18, 2015	- -

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

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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

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. -

Charcot-Marie-Tooth disease dominant intermediate B;C4551952:Autosomal dominant centronuclear myopathy;C4706410:Fetal akinesia-cerebral and retinal hemorrhage syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 11, 2022

- -

DNM2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 25, 2021

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
Cadd	Benign	0.81
Dann	Benign	0.55
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000046
dbscSNV1_RF	Benign	0.010
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: rs201979143; hg19: chr19-10941061;