rs145478270

chr19-10777171-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001005361.3(DNM2):c.643G>A(p.Asp215Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000842 in 1,614,186 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D215E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0016 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00076 (6 hom.)
• Consequence: DNM2 NM_001005361.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 9.89

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 -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, DNM2
• BP4: Computational evidence support a benign effect (MetaRNN=0.015476167).
• BP6: Variant 19-10777171-G-A is Benign according to our data. Variant chr19-10777171-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 416987.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0016 (243/152306) while in subpopulation NFE AF= 0.00119 (81/68026). AF 95% confidence interval is 0.000981. There are 1 homozygotes in gnomad4. There are 175 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNM2	NM_001005361.3	c.643G>A	p.Asp215Asn	missense_variant	5/21	ENST00000389253.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNM2	ENST00000389253.9	c.643G>A	p.Asp215Asn	missense_variant	5/21	5	NM_001005361.3	A1

Frequencies

GnomAD3 genomes AF: 0.00160 AC: 243 AN: 152188 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0145

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00119

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00162 AC: 407 AN: 251426 Hom.: 2 AF XY: 0.00154 AC XY: 209 AN XY: 135886

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.0127

Gnomad NFE exome AF: 0.000967

Gnomad OTH exome AF: 0.00244

GnomAD4 exome AF: 0.000763 AC: 1116 AN: 1461880 Hom.: 6 Cov.: 31 AF XY: 0.000776 AC XY: 564 AN XY: 727234

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000255

Gnomad4 FIN exome AF: 0.0111

Gnomad4 NFE exome AF: 0.000396

Gnomad4 OTH exome AF: 0.000778

GnomAD4 genome AF: 0.00160 AC: 243 AN: 152306 Hom.: 1 Cov.: 32 AF XY: 0.00235 AC XY: 175 AN XY: 74470

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.0145

Gnomad4 NFE AF: 0.00119

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000729 Hom.: 1

Bravo AF: 0.000317

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00150 AC: 182

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000771

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	DNM2: PP3, BP5, BS2 -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 20, 2018	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 06, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Charcot-Marie-Tooth disease dominant intermediate B Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

DNM2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 08, 2019

This variant is classified as 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	0.31
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.18
Cadd	Pathogenic	33
Dann	Uncertain	1.0
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.21
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;D;D;D
MetaRNN	Benign	0.015	T;T;T;T;T
MetaSVM	Uncertain	0.74	D
MutationAssessor	Benign	1.8	L;L;L;L;L
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Pathogenic	0.79	T
Sift4G	Benign	0.28	T;T;T;T;T
Polyphen		0.51, 0.94	.;P;.;P;.
Vest4		0.64
MVP		0.96
MPC		1.8
ClinPred		0.053	T
GERP RS		3.9
Varity_R		0.32
gMVP		0.85

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: rs145478270; hg19: chr19-10887847;