chr19-10786672-G-A

Variant names:

• chr19-10786672-G-A
• rs150613209
• NM_001005361.3:c.958G>A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2 BP4_Moderate BP6 BS1

The NM_001005361.3(DNM2):​c.958G>A​(p.Asp320Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000638 in 1,614,034 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 0.00024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000045 (0 hom.)
• Consequence: DNM2 NM_001005361.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:6
• Conservation: PhyloP100: 10.0

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 Likely_benign. Variant got -6 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.14517361).
• BP6: Variant 19-10786672-G-A is Benign according to our data. Variant chr19-10786672-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 158529.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=3, Likely_benign=3}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.0000451 (66/1461868) while in subpopulation AFR AF= 0.00105 (35/33480). AF 95% confidence interval is 0.000772. There are 0 homozygotes in gnomad4_exome. There are 25 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNM2	NM_001005361.3	c.958G>A	p.Asp320Asn	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.958G>A	p.Asp320Asn	missense_variant	Exon 7 of 21	5	NM_001005361.3	ENSP00000373905.4

Frequencies

GnomAD3 genomes AF: 0.000243 AC: 37 AN: 152048 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000701

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

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: 0.000960

GnomAD3 exomes AF: 0.000111 AC: 28 AN: 251208 Hom.: 0 AF XY: 0.000103 AC XY: 14 AN XY: 135854

Gnomad AFR exome AF: 0.000862

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000359

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000451 AC: 66 AN: 1461868 Hom.: 0 Cov.: 31 AF XY: 0.0000344 AC XY: 25 AN XY: 727238

Gnomad4 AFR exome AF: 0.00105

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.000174

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.0000662

GnomAD4 genome AF: 0.000243 AC: 37 AN: 152166 Hom.: 0 Cov.: 32 AF XY: 0.000242 AC XY: 18 AN XY: 74398

Gnomad4 AFR AF: 0.000699

Gnomad4 AMR AF: 0.000392

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: 0.000950

Alfa AF: 0.000193 Hom.: 0

Bravo AF: 0.000295

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000115 AC: 14

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Jun 14, 2017

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Asp320Asn variant (rs150613209) has not been reported in the medical literature, nor has it been previously identified in our laboratory; however, it is listed in the ClinVar database (Variation ID: 158529). This variant is listed in the Genome Aggregation Database (gnomAD) browser with an overall frequency of 0.01% (identified in 33 out of 276,996 chromosomes). The aspartic acid at codon 320 is moderately conserved considering 14 species (Alamut software v2.9), and computational analyses return mixed results regarding the effect of this variant on DNM2 protein structure/function (SIFT: tolerated, PolyPhen2: benign, and Mutation Taster: disease causing). Therefore, based on the available information, the clinical significance of the p.Asp320Asn variant cannot be determined with certainty. -

Jan 18, 2024

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:2

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 16, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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:2

Nov 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Autosomal dominant centronuclear myopathy Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Inborn genetic diseases Benign:1

Oct 26, 2022

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	Benign	0.31
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.35
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.72	.;.;.;D;.;D
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D
M_CAP	Benign	0.079	D
MetaRNN	Benign	0.15	T;T;T;T;T;T
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Benign	1.9	L;L;L;L;L;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-2.2	.;N;N;N;N;.
REVEL	Benign	0.27
Sift	Benign	0.30	.;T;T;T;T;.
Sift4G	Benign	0.25	T;T;T;T;T;T
Polyphen		0.0090, 0.010	.;B;.;B;.;.
Vest4		0.81
MVP		0.86
MPC		1.2
ClinPred		0.065	T
GERP RS		5.0
Varity_R		0.26
gMVP		0.46

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: rs150613209; hg19: chr19-10897348;