19-10783110-C-T

Position:

chr19-10783110-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP2BP4_Moderate

The NM_001005361.3(DNM2):c.839C>T(p.Thr280Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000335 in 1,611,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

DNM2
NM_001005361.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 6.07

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 Likely_benign. Variant got -1 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), DNM2. . Gene score misZ 3.4829 (greater than the threshold 3.09). Trascript score misZ 4.8575 (greater than threshold 3.09). GenCC has associacion of gene with fetal akinesia-cerebral and retinal hemorrhage syndrome, Charcot-Marie-Tooth disease dominant intermediate B, hereditary spastic paraplegia, Charcot-Marie-Tooth disease, autosomal dominant centronuclear myopathy, autosomal dominant Charcot-Marie-Tooth disease type 2M.

BP4

Computational evidence support a benign effect (MetaRNN=0.14245668).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNM2	NM_001005361.3 linkuse as main transcript	c.839C>T	p.Thr280Met	missense_variant	6/21	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.839C>T	p.Thr280Met	missense_variant	6/21	5	NM_001005361.3	ENSP00000373905.4		P50570-4

Frequencies

GnomAD3 genomes

AF:

0.000138

AC:

AN:

152254

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000506

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000444

AC:

AN:

247890

Hom.:

AF XY:

0.0000372

AC XY:

AN XY:

134314

show subpopulations

Gnomad AFR exome

AF:

0.000494

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000178

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000226

AC:

AN:

1459514

Hom.:

Cov.:

AF XY:

0.0000179

AC XY:

AN XY:

726106

show subpopulations

Gnomad4 AFR exome

AF:

0.000538

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000809

Gnomad4 OTH exome

AF:

0.0000663

GnomAD4 genome

AF:

0.000138

AC:

AN:

152372

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74508

show subpopulations

Gnomad4 AFR

AF:

0.000505

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:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00000593

Hom.:

Bravo

AF:

0.000144

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000494

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 08, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 26, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 31, 2016	The T280M variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The 1000 Genomes Project Consortium reports T280M was observed in 2/122 alleles from Americans of African ancestry in the Southwest USA. The T280M variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

Charcot-Marie-Tooth disease dominant intermediate B

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 09, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.060

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.17

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.61

.;.;.;D;.;T

Eigen

Uncertain

0.32

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.89

D;D;D;D;D;D

M_CAP

Benign

0.059

MetaRNN

Benign

0.14

T;T;T;T;T;T

MetaSVM

Uncertain

-0.16

MutationAssessor

Uncertain

2.1

M;M;M;M;M;.

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-0.17

.;N;N;N;N;.

REVEL

Benign

0.26

Sift

Benign

0.046

.;D;D;D;D;.

Sift4G

Benign

0.10

T;T;T;T;T;T

Polyphen

0.028, 0.28

.;B;.;B;.;.

Vest4

0.42

MVP

0.63

MPC

1.1

ClinPred

0.11

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.076

gMVP

0.42

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