19-10718283-A-G

Variant names:

• chr19-10718283-A-G
• rs2145637630
• NM_001005361.3:c.41A>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001005361.3(DNM2):​c.41A>G​(p.Asn14Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000297 in 1,346,630 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000030 (0 hom.)
• Consequence: DNM2 NM_001005361.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.11
• Publications: 0 publications found

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]

MIR638 (HGNC:32894): (microRNA 638) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.887

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNM2	NM_001005361.3	c.41A>G	p.Asn14Ser	missense_variant	Exon 1 of 21	ENST00000389253.9	NP_001005361.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNM2	ENST00000389253.9	c.41A>G	p.Asn14Ser	missense_variant	Exon 1 of 21	5	NM_001005361.3	ENSP00000373905.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000297 AC: 4 AN: 1346630 Hom.: 0 Cov.: 31 AF XY: 0.00000150 AC XY: 1 AN XY: 664812

African (AFR) AF: 0.00 AC: 0 AN: 27658

American (AMR) AF: 0.00 AC: 0 AN: 29350

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23472

East Asian (EAS) AF: 0.00 AC: 0 AN: 29510

South Asian (SAS) AF: 0.00 AC: 0 AN: 74224

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47648

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3950

European-Non Finnish (NFE) AF: 0.00000379 AC: 4 AN: 1055466

Other (OTH) AF: 0.00 AC: 0 AN: 55352

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Jun 13, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (gnomAD no frequency). 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with DNM2-related conditions. This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 14 of the DNM2 protein (p.Asn14Ser). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.87	.;.;.;D;.
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.89	D;D;D;D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	3.0	M;M;M;M;M
PhyloP100		8.1
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-4.2	.;D;D;D;D
REVEL	Pathogenic	0.78
Sift	Pathogenic	0.0	.;D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D
Polyphen		1.0, 1.0	.;D;.;D;.
Vest4		0.67
MutPred		0.74		Gain of ubiquitination at K15 (P = 0.0575);Gain of ubiquitination at K15 (P = 0.0575);Gain of ubiquitination at K15 (P = 0.0575);Gain of ubiquitination at K15 (P = 0.0575);Gain of ubiquitination at K15 (P = 0.0575);
MVP		0.97
MPC		1.9
ClinPred		1.0	D
GERP RS		4.1
PromoterAI		-0.090	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.82
gMVP		0.82
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2145637630; hg19: chr19-10828959;