rs3826803

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -1.02

Publications

14 publications found

Variant links:

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

DNM2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 256866.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 link	c.236-29C>G		intron_variant	Intron 2 of 20	ENST00000389253.9	NP_001005361.1	P50570-4Q8N1K8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNM2	ENST00000389253.9 link	c.236-29C>G		intron_variant	Intron 2 of 20	5	NM_001005361.3	ENSP00000373905.4		P50570-4

Frequencies

GnomAD3 genomes

AF:

0.564

AC:

85604

AN:

151870

Hom.:

24325

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.553

AC:

138398

AN:

250432

AF XY:

0.550

show subpopulations

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 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.:

AF XY:

0.537

AC XY:

389893

AN XY:

726490

show subpopulations

African (AFR)

AF:

0.600

AC:

20089

AN:

33456

American (AMR)

AF:

0.647

AC:

28908

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.488

AC:

12761

AN:

26124

East Asian (EAS)

AF:

0.445

AC:

17645

AN:

39678

South Asian (SAS)

AF:

0.573

AC:

49431

AN:

86236

European-Finnish (FIN)

AF:

0.536

AC:

28191

AN:

52636

Middle Eastern (MID)

AF:

0.452

AC:

2602

AN:

5760

European-Non Finnish (NFE)

AF:

0.532

AC:

591770

AN:

1111320

Other (OTH)

AF:

0.530

AC:

31981

AN:

60358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

19350

38699

58049

77398

96748

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16872

33744

50616

67488

84360

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.563

AC:

85629

AN:

151990

Hom.:

24329

Cov.:

AF XY:

0.563

AC XY:

41792

AN XY:

74266

show subpopulations

African (AFR)

AF:

0.607

AC:

25172

AN:

41464

American (AMR)

AF:

0.612

AC:

9331

AN:

15248

Ashkenazi Jewish (ASJ)

AF:

0.496

AC:

1721

AN:

3468

East Asian (EAS)

AF:

0.440

AC:

2269

AN:

5160

South Asian (SAS)

AF:

0.583

AC:

2811

AN:

4818

European-Finnish (FIN)

AF:

0.526

AC:

5546

AN:

10546

Middle Eastern (MID)

AF:

0.422

AC:

124

AN:

294

European-Non Finnish (NFE)

AF:

0.545

AC:

37012

AN:

67974

Other (OTH)

AF:

0.553

AC:

1165

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1942

3885

5827

7770

9712

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

730

1460

2190

2920

3650

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

LINK: link

Submissions by phenotype

not provided

Benign:2

Jun 23, 2018

GeneDx

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

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal dominant centronuclear myopathy

Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Charcot-Marie-Tooth disease dominant intermediate B

Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Fetal akinesia-cerebral and retinal hemorrhage syndrome

Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

0.55

(source)

DANN

Benign

0.59

PhyloP100

-1.0

BranchPoint Hunter

2.0

Mutation Taster

=16/84

disease causing (long InDel)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over