rs1008731390

Variant names:

• chr19-10718261-G-C
• rs1008731390
• NM_001005361.3:c.19G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001005361.3(DNM2):​c.19G>C​(p.Glu7Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000015 in 1,335,916 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E7G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: DNM2 NM_001005361.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.70
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001005361.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNM2	NM_001005361.3	MANE Select	c.19G>C	p.Glu7Gln	missense	Exon 1 of 21	NP_001005361.1	P50570-4
	DNM2	NM_001005360.3		c.19G>C	p.Glu7Gln	missense	Exon 1 of 21	NP_001005360.1	P50570-1
	DNM2	NM_001190716.2		c.19G>C	p.Glu7Gln	missense	Exon 1 of 21	NP_001177645.1	P50570-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNM2	ENST00000389253.9	TSL:5 MANE Select	c.19G>C	p.Glu7Gln	missense	Exon 1 of 21	ENSP00000373905.4	P50570-4
	DNM2	ENST00000355667.11	TSL:1	c.19G>C	p.Glu7Gln	missense	Exon 1 of 21	ENSP00000347890.6	P50570-1
	DNM2	ENST00000585892.5	TSL:1	c.19G>C	p.Glu7Gln	missense	Exon 1 of 21	ENSP00000468734.1	P50570-5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000150 AC: 2 AN: 1335916 Hom.: 0 Cov.: 31 AF XY: 0.00000152 AC XY: 1 AN XY: 659006

African (AFR) AF: 0.0000370 AC: 1 AN: 27044

American (AMR) AF: 0.00 AC: 0 AN: 28464

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23312

East Asian (EAS) AF: 0.00 AC: 0 AN: 28442

South Asian (SAS) AF: 0.00 AC: 0 AN: 73392

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46842

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3924

European-Non Finnish (NFE) AF: 9.53e-7 AC: 1 AN: 1049666

Other (OTH) AF: 0.00 AC: 0 AN: 54830

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Charcot-Marie-Tooth disease dominant intermediate B (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	32
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.48	T
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.73	D
MetaRNN	Uncertain	0.50	T
MetaSVM	Pathogenic	0.84	D
MutationAssessor	Benign	1.9	L
PhyloP100		8.7
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.2	N
REVEL	Pathogenic	0.75
Sift	Benign	0.20	T
Sift4G	Benign	0.18	T
Polyphen		1.0	D
Vest4		0.36
MutPred		0.38		Gain of helix (P = 0.0696)
MVP		0.92
MPC		1.2
ClinPred		0.92	D
GERP RS		4.1
PromoterAI		-0.12	Neutral
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Varity_R		0.51
gMVP		0.73
Mutation Taster		=72/28	polymorphism

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

Other links and lift over

dbSNP: rs1008731390; hg19: chr19-10828937;