9-128250826-C-G

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 1P and 3B. PP2BP4_ModerateBP6

The NM_004408.4(DNM1):c.2420C>G(p.Ser807Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000594 in 1,324,334 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).

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00064 ( 1 hom. )

Consequence

DNM1
NM_004408.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: 5.42

Variant links:

Genes affected

DNM1 (HGNC:2972): (dynamin 1) This gene encodes a member of the dynamin subfamily of GTP-binding proteins. The encoded protein possesses unique mechanochemical properties used to tubulate and sever membranes, and is involved in clathrin-mediated endocytosis and other vesicular trafficking processes. Actin and other cytoskeletal proteins act as binding partners for the encoded protein, which can also self-assemble leading to stimulation of GTPase activity. More than sixty highly conserved copies of the 3' region of this gene are found elsewhere in the genome, particularly on chromosomes Y and 15. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

DNM1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PP2

Missense variant in the DNM1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 39 curated pathogenic missense variants (we use a threshold of 10). The gene has 46 curated benign missense variants. Gene score misZ: 5.1795 (above the threshold of 3.09). Trascript score misZ: 5.021 (above the threshold of 3.09). GenCC associations: The gene is linked to developmental and epileptic encephalopathy, 31, undetermined early-onset epileptic encephalopathy, developmental and epileptic encephalopathy 31B, developmental and epileptic encephalopathy, Lennox-Gastaut syndrome.

BP4

Computational evidence support a benign effect (MetaRNN=0.19125956).

BP6

Variant 9-128250826-C-G is Benign according to our data. Variant chr9-128250826-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 387422.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=1, Uncertain_significance=1}. Variant chr9-128250826-C-G is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNM1	NM_004408.4 link	c.2420C>G	p.Ser807Cys	missense_variant	Exon 21 of 22	ENST00000372923.8	NP_004399.2	Q05193-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNM1	ENST00000372923.8 link	c.2420C>G	p.Ser807Cys	missense_variant	Exon 21 of 22	1	NM_004408.4	ENSP00000362014.4		Q05193-1
DNM1	ENST00000634267.2 link	c.2420C>G	p.Ser807Cys	missense_variant	Exon 21 of 22	5		ENSP00000489096.1		A0A0U1RQP1

Frequencies

GnomAD3 genomes

AF:

0.000217

AC:

AN:

151980

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000383

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.000642

AC:

753

AN:

1172246

Hom.:

Cov.:

AF XY:

0.000588

AC XY:

333

AN XY:

566404

show subpopulations

Gnomad4 AFR exome

AF:

0.0000428

Gnomad4 AMR exome

AF:

0.000112

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:

0.000712

Gnomad4 OTH exome

AF:

0.00110

GnomAD4 genome

AF:

0.000217

AC:

AN:

152088

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000383

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000347

Hom.:

Bravo

AF:

0.000283

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Nov 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DNM1: PP2 -

May 06, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Developmental and epileptic encephalopathy, 31A

Benign:1

Dec 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases

Benign:1

Aug 14, 2023

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. -

DNM1-related disorder

Benign:1

Aug 30, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.41

CADD

Pathogenic

DANN

Benign

0.97

DEOGEN2

Benign

0.32

T;.;.;.;.;.;T;.;.

Eigen

Benign

0.086

Eigen_PC

Benign

0.12

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.92

D;.;.;D;D;D;D;D;D

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.19

T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.8

L;L;L;L;.;L;.;L;.

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

-1.1

N;N;N;N;.;N;.;.;.

REVEL

Benign

0.11

Sift

Benign

0.042

D;D;D;D;.;D;.;.;.

Sift4G

Uncertain

0.056

T;T;T;T;T;T;T;T;T

Polyphen

0.88

P;.;P;.;.;.;.;P;.

Vest4

0.25

MutPred

0.40

Gain of catalytic residue at S807 (P = 0.0042);Gain of catalytic residue at S807 (P = 0.0042);Gain of catalytic residue at S807 (P = 0.0042);Gain of catalytic residue at S807 (P = 0.0042);.;Gain of catalytic residue at S807 (P = 0.0042);.;Gain of catalytic residue at S807 (P = 0.0042);Gain of catalytic residue at S807 (P = 0.0042);

MVP

0.34

MPC

1.3

ClinPred

0.36

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.18

gMVP

0.075

Splicing

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