rs760254039

Variant names:

• chr19-10786603-C-T
• rs760254039
• NM_001005361.3:c.889C>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PP2 PP3_Moderate BP6

The NM_001005361.3(DNM2):​c.889C>T​(p.Arg297Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000211 in 1,614,026 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: DNM2 NM_001005361.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 4.88

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 Uncertain_significance. Variant got 2 ACMG points.

• PP2: Missense variant in the DNM2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 30 curated pathogenic missense variants (we use a threshold of 10). The gene has 14 curated benign missense variants. Gene score misZ: 3.4829 (above the threshold of 3.09). Trascript score misZ: 4.8575 (above the threshold of 3.09). GenCC associations: The gene is linked to 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.9
• BP6: Variant 19-10786603-C-T is Benign according to our data. Variant chr19-10786603-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 533827.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNM2	NM_001005361.3	c.889C>T	p.Arg297Cys	missense_variant	Exon 7 of 21	ENST00000389253.9	NP_001005361.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNM2	ENST00000389253.9	c.889C>T	p.Arg297Cys	missense_variant	Exon 7 of 21	5	NM_001005361.3	ENSP00000373905.4

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152134 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000597 AC: 15 AN: 251402 Hom.: 0 AF XY: 0.0000515 AC XY: 7 AN XY: 135914

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.0000704

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000212 AC: 31 AN: 1461892 Hom.: 0 Cov.: 32 AF XY: 0.0000220 AC XY: 16 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000243

Gnomad4 NFE exome AF: 0.0000135

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152134 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74294

Gnomad4 AFR AF: 0.00

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: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000329 Hom.: 0

ExAC AF: 0.0000824 AC: 10

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Jul 07, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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: 533827). This variant has not been reported in the literature in individuals affected with DNM2-related conditions. This variant is present in population databases (rs760254039, gnomAD 0.02%), and has an allele count higher than expected for a pathogenic variant. This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 297 of the DNM2 protein (p.Arg297Cys). -

not provided Uncertain:1

Jun 03, 2019

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Benign:1

Sep 02, 2020

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.93	.;.;.;D;.;D
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.90	D;D;D;D;D;D
MetaSVM	Uncertain	0.57	D
MutationAssessor	Pathogenic	3.4	M;M;M;M;M;.
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-7.5	.;D;D;D;D;.
REVEL	Pathogenic	0.72
Sift	Pathogenic	0.0	.;D;D;D;D;.
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D
Polyphen		1.0, 1.0	.;D;.;D;.;.
Vest4		0.88
MVP		0.88
MPC		2.5
ClinPred		0.97	D
GERP RS		5.0
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Varity_R		0.90
gMVP		0.71

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: rs760254039; hg19: chr19-10897279;