rs375151459

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_ModerateBP6

The NM_001005361.3(DNM2):c.316G>A(p.Asp106Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000083 in 1,614,142 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D106Y) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000081 ( 1 hom. )

Consequence

DNM2
NM_001005361.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 9.99

Publications

2 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: Likely_benign. The variant received -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.1957084).

BP6

Variant 19-10772559-G-A is Benign according to our data. Variant chr19-10772559-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 246522. Variant chr19-10772559-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 246522. Variant chr19-10772559-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 246522. Variant chr19-10772559-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 246522. Variant chr19-10772559-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 246522. Variant chr19-10772559-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 246522. Variant chr19-10772559-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 246522. Variant chr19-10772559-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 246522. Variant chr19-10772559-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 246522. Variant chr19-10772559-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 246522. Variant chr19-10772559-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 246522. Variant chr19-10772559-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 246522. Variant chr19-10772559-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 246522. Variant chr19-10772559-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 246522. Variant chr19-10772559-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 246522. Variant chr19-10772559-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 246522. Variant chr19-10772559-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 246522. Variant chr19-10772559-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 246522. Variant chr19-10772559-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 246522. Variant chr19-10772559-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 246522. Variant chr19-10772559-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 246522. Variant chr19-10772559-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 246522. Variant chr19-10772559-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 246522. Variant chr19-10772559-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 246522. Variant chr19-10772559-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 246522. Variant chr19-10772559-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 246522. Variant chr19-10772559-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 246522. Variant chr19-10772559-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 246522. Variant chr19-10772559-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 246522. Variant chr19-10772559-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 246522. Variant chr19-10772559-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 246522. Variant chr19-10772559-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 246522. Variant chr19-10772559-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 246522. Variant chr19-10772559-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 246522. Variant chr19-10772559-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 246522. Variant chr19-10772559-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 246522. Variant chr19-10772559-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 246522. Variant chr19-10772559-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 246522. Variant chr19-10772559-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 246522. Variant chr19-10772559-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 246522. Variant chr19-10772559-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 246522. Variant chr19-10772559-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 246522.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNM2	NM_001005361.3 link	c.316G>A	p.Asp106Asn	missense_variant	Exon 3 of 21	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.316G>A	p.Asp106Asn	missense_variant	Exon 3 of 21	5	NM_001005361.3	ENSP00000373905.4		P50570-4

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000770

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000175

AC:

AN:

251454

AF XY:

0.000132

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00158

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000106

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000807

AC:

118

AN:

1461882

Hom.:

Cov.:

AF XY:

0.0000839

AC XY:

AN XY:

727240

show subpopulations

African (AFR)

AF:

0.000119

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.000630

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000710

AC:

AN:

1112010

Other (OTH)

AF:

0.000149

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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:

0.000105

AC:

AN:

152260

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.000168

AC:

AN:

41572

American (AMR)

AF:

0.00

AC:

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000771

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10592

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000148

Hom.:

Bravo

AF:

0.000147

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000157

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Jan 05, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 11, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 31571979) -

Inborn genetic diseases

Benign:1

Oct 28, 2019

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Charcot-Marie-Tooth disease dominant intermediate B

Benign:1

Sep 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.12

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.95

.;.;.;D;.

Eigen

Pathogenic

0.73

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

D;D;D;D;D

M_CAP

Pathogenic

0.31

MetaRNN

Benign

0.20

T;T;T;T;T

MetaSVM

Pathogenic

1.0

MutationAssessor

Benign

1.4

L;L;L;L;L

PhyloP100

PrimateAI

Uncertain

0.78

PROVEAN

Uncertain

-4.1

.;D;D;D;D

REVEL

Pathogenic

0.66

Sift

Benign

0.033

.;D;D;D;D

Sift4G

Uncertain

0.049

D;D;D;D;D

Polyphen

0.92, 1.0

.;P;.;D;.

Vest4

0.66

MVP

0.91

MPC

2.0

ClinPred

0.27

GERP RS

5.5

Varity_R

0.33

gMVP

0.81

Mutation Taster

=99/1

polymorphism

(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