rs3826803

Variant names:

• chr19-10772450-C-G
• rs3826803
• NM_001005361.3:c.236-29C>G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001005361.3(DNM2):​c.236-29C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.539 in 1,612,272 control chromosomes in the GnomAD database, including 235,521 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.56 (24329 hom., cov: 31)
  • Exomes 𝑓: 0.54 (211192 hom.)
• Consequence: DNM2 NM_001005361.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.02

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: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 2 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 19-10772450-C-G is Benign according to our data. Variant chr19-10772450-C-G is described in ClinVar as [Benign]. Clinvar id is 256866.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-10772450-C-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.602 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNM2	NM_001005361.3	c.236-29C>G		intron_variant	Intron 2 of 20	ENST00000389253.9	NP_001005361.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNM2	ENST00000389253.9	c.236-29C>G		intron_variant	Intron 2 of 20	5	NM_001005361.3	ENSP00000373905.4

Frequencies

GnomAD3 genomes AF: 0.564 AC: 85604 AN: 151870 Hom.: 24325 Cov.: 31

Gnomad AFR AF: 0.608

Gnomad AMI AF: 0.525

Gnomad AMR AF: 0.612

Gnomad ASJ AF: 0.496

Gnomad EAS AF: 0.440

Gnomad SAS AF: 0.584

Gnomad FIN AF: 0.526

Gnomad MID AF: 0.418

Gnomad NFE AF: 0.544

Gnomad OTH AF: 0.554

GnomAD3 exomes AF: 0.553 AC: 138398 AN: 250432 Hom.: 38709 AF XY: 0.550 AC XY: 74530 AN XY: 135504

Gnomad AFR exome AF: 0.606

Gnomad AMR exome AF: 0.650

Gnomad ASJ exome AF: 0.487

Gnomad EAS exome AF: 0.456

Gnomad SAS exome AF: 0.572

Gnomad FIN exome AF: 0.537

Gnomad NFE exome AF: 0.536

Gnomad OTH exome AF: 0.528

GnomAD4 exome AF: 0.536 AC: 783378 AN: 1460282 Hom.: 211192 Cov.: 46 AF XY: 0.537 AC XY: 389893 AN XY: 726490

Gnomad4 AFR exome AF: 0.600

Gnomad4 AMR exome AF: 0.647

Gnomad4 ASJ exome AF: 0.488

Gnomad4 EAS exome AF: 0.445

Gnomad4 SAS exome AF: 0.573

Gnomad4 FIN exome AF: 0.536

Gnomad4 NFE exome AF: 0.532

Gnomad4 OTH exome AF: 0.530

GnomAD4 genome AF: 0.563 AC: 85629 AN: 151990 Hom.: 24329 Cov.: 31 AF XY: 0.563 AC XY: 41792 AN XY: 74266

Gnomad4 AFR AF: 0.607

Gnomad4 AMR AF: 0.612

Gnomad4 ASJ AF: 0.496

Gnomad4 EAS AF: 0.440

Gnomad4 SAS AF: 0.583

Gnomad4 FIN AF: 0.526

Gnomad4 NFE AF: 0.545

Gnomad4 OTH AF: 0.553

Alfa AF: 0.547 Hom.: 4199

Bravo AF: 0.567

Asia WGS AF: 0.544 AC: 1890 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 23, 2018	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Autosomal dominant centronuclear myopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Charcot-Marie-Tooth disease dominant intermediate B Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Fetal akinesia-cerebral and retinal hemorrhage syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.55
DANN	Benign	0.59
BranchPoint Hunter		2.0

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: rs3826803; hg19: chr19-10883126; COSMIC: COSV58957282; COSMIC: COSV58957282;