rs148790687

chr19-10772481-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2 BP4_Strong BP6_Very_Strong BS1

The NM_001005361.3(DNM2):c.238C>T(p.His80Tyr) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00186 in 1,614,112 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (1 hom.)
• Consequence: DNM2 NM_001005361.3 missense, splice_region
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 4.24

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]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• PP2: Missense variant where missense usually causes diseases, DNM2
• BP4: Computational evidence support a benign effect (MetaRNN=0.011853009).
• BP6: Variant 19-10772481-C-T is Benign according to our data. Variant chr19-10772481-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 137130.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-10772481-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00119 (182/152322) while in subpopulation NFE AF= 0.00213 (145/68040). AF 95% confidence interval is 0.00185. There are 0 homozygotes in gnomad4. There are 79 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNM2	NM_001005361.3	c.238C>T	p.His80Tyr	missense_variant, splice_region_variant	3/21	ENST00000389253.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNM2	ENST00000389253.9	c.238C>T	p.His80Tyr	missense_variant, splice_region_variant	3/21	5	NM_001005361.3	A1

Frequencies

GnomAD3 genomes AF: 0.00119 AC: 181 AN: 152204 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.000753

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00213

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00108 AC: 272 AN: 251382 Hom.: 1 AF XY: 0.00121 AC XY: 165 AN XY: 135866

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00147

Gnomad FIN exome AF: 0.000510

Gnomad NFE exome AF: 0.00178

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00193 AC: 2818 AN: 1461790 Hom.: 1 Cov.: 34 AF XY: 0.00189 AC XY: 1371 AN XY: 727204

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00126

Gnomad4 FIN exome AF: 0.000581

Gnomad4 NFE exome AF: 0.00227

Gnomad4 OTH exome AF: 0.00235

GnomAD4 genome AF: 0.00119 AC: 182 AN: 152322 Hom.: 0 Cov.: 32 AF XY: 0.00106 AC XY: 79 AN XY: 74482

Gnomad4 AFR AF: 0.000481

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.000753

Gnomad4 NFE AF: 0.00213

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00180 Hom.: 0

Bravo AF: 0.00118

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00244 AC: 21

ExAC AF: 0.000955 AC: 116

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00218

EpiControl AF: 0.00207

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 07, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -

Charcot-Marie-Tooth disease dominant intermediate B Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	DNM2: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 06, 2023	- -

Autosomal dominant centronuclear myopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

DNM2-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 30, 2021

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). -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 26, 2019

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.026
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.20
Cadd	Benign	14
Dann	Benign	0.36
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.39	N
LIST_S2	Benign	0.72	T;T;T;T;T
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.012	T;T;T;T;T
MetaSVM	Benign	-0.37	T
MutationAssessor	Benign	-2.3	N;N;N;N;N
MutationTaster	Benign	0.74	N;N;N;N;N;N
PrimateAI	Uncertain	0.79	T
Sift4G	Benign	1.0	T;T;T;T;T
Polyphen		0.0	.;B;.;B;.
Vest4		0.27
MVP		0.41
MPC		1.1
ClinPred		0.0021	T
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.018
gMVP		0.48

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

Other links and lift over

dbSNP: rs148790687; hg19: chr19-10883157; COSMIC: COSV58962777; COSMIC: COSV58962777;