19-10718250-A-G

Position:

chr19-10718250-A-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The c.8A>G variant in DNM2 is a missense variant predicted to cause substitution of asparagine by serine at amino acid 3. The highest population filtering allele frequency in gnomAD v4.1 is 0.00001190 (2/43076 alleles) in the Admixed American population, which is higher than the ClinGen Congenital Myopathies VCEP threshold (≥0.0000015) for BA1, and therefore meets this criterion (BA1). The computational predictor REVEL gives a score of 0.57, which is neither above nor below the thresholds predicting a damaging or benign impact on DNM2 function. DNM2, in which the variant was identified, is defined by the ClinGen Congenital Myopathies VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2, not applied for this variant due to high allele frequency). In summary, this variant meets the criteria to be classified as benign for autosomal dominant centronuclear myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: BA1. (Congenital Myopathies VCEP specifications version 1; 8/7/24) LINK:https://erepo.genome.network/evrepo/ui/classification/CA16620725/MONDO:0018947/148

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

DNM2
NM_001005361.3 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:5B:1

Conservation

PhyloP100: 4.91

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 links:

DNM2 (HGNC:):

DNM2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BA1

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNM2	NM_001005361.3 linkuse as main transcript	c.8A>G	p.Asn3Ser	missense_variant	1/21	ENST00000389253.9	NP_001005361.1	P50570-4Q8N1K8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNM2	ENST00000389253.9 linkuse as main transcript	c.8A>G	p.Asn3Ser	missense_variant	1/21	5	NM_001005361.3	ENSP00000373905.4		P50570-4

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

151958

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000725

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000105

AC:

AN:

95144

Hom.:

AF XY:

0.00

AC XY:

AN XY:

52872

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000588

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000120

AC:

AN:

1329002

Hom.:

Cov.:

AF XY:

0.00000916

AC XY:

AN XY:

655332

show subpopulations

Gnomad4 AFR exome

AF:

0.0000373

Gnomad4 AMR exome

AF:

0.0000719

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000105

Gnomad4 OTH exome

AF:

0.0000367

GnomAD4 genome

AF:

0.0000329

AC:

AN:

151958

Hom.:

Cov.:

AF XY:

0.0000539

AC XY:

AN XY:

74244

show subpopulations

Gnomad4 AFR

AF:

0.0000725

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000297

Hom.:

Bravo

AF:

0.0000302

ClinVar

Significance: Benign

Submissions summary: Uncertain:5Benign:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 01, 2019	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 08, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 14, 2020	- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 29, 2022

The c.8A>G (p.N3S) alteration is located in exon 1 (coding exon 1) of the DNM2 gene. This alteration results from a A to G substitution at nucleotide position 8, causing the asparagine (N) at amino acid position 3 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Charcot-Marie-Tooth disease dominant intermediate B

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 02, 2022

The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on DNM2 protein function. ClinVar contains an entry for this variant (Variation ID: 424401). This variant has not been reported in the literature in individuals affected with DNM2-related conditions. This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 3 of the DNM2 protein (p.Asn3Ser). -

Centronuclear myopathy

Benign:1

Benign, reviewed by expert panel

curation

ClinGen Congenital Myopathies Variant Curation Expert Panel, ClinGen

Aug 07, 2024

The c.8A>G variant in DNM2 is a missense variant predicted to cause substitution of asparagine by serine at amino acid 3. The highest population filtering allele frequency in gnomAD v4.1 is 0.00001190 (2/43076 alleles) in the Admixed American population, which is higher than the ClinGen Congenital Myopathies VCEP threshold (≥0.0000015) for BA1, and therefore meets this criterion (BA1). The computational predictor REVEL gives a score of 0.57, which is neither above nor below the thresholds predicting a damaging or benign impact on DNM2 function. DNM2, in which the variant was identified, is defined by the ClinGen Congenital Myopathies VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2, not applied for this variant due to high allele frequency). In summary, this variant meets the criteria to be classified as benign for autosomal dominant centronuclear myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: BA1. (Congenital Myopathies VCEP specifications version 1; 8/7/24) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.44

BayesDel_addAF

Uncertain

0.079

BayesDel_noAF

Benign

-0.12

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.78

.;.;.;D;.

Eigen

Uncertain

0.39

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Uncertain

0.91

LIST_S2

Pathogenic

1.0

D;D;D;D;D

M_CAP

Pathogenic

0.87

MetaRNN

Uncertain

0.45

T;T;T;T;T

MetaSVM

Pathogenic

0.89

MutationAssessor

Uncertain

2.2

M;M;M;M;M

MutationTaster

Benign

1.0

D;D;D;D;D;D

PrimateAI

Uncertain

0.75

PROVEAN

Uncertain

-3.4

.;D;D;D;D

REVEL

Uncertain

0.57

Sift

Uncertain

0.0020

.;D;D;D;D

Sift4G

Benign

0.092

T;T;T;T;T

Polyphen

1.0, 1.0

.;D;.;D;.

Vest4

0.21

MutPred

0.28

Gain of phosphorylation at N3 (P = 0.0265);Gain of phosphorylation at N3 (P = 0.0265);Gain of phosphorylation at N3 (P = 0.0265);Gain of phosphorylation at N3 (P = 0.0265);Gain of phosphorylation at N3 (P = 0.0265);

MVP

0.96

MPC

1.9

ClinPred

0.96

GERP RS

2.9

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.8

Varity_R

0.63

gMVP

0.66

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over