19-10718246-G-T

Variant names:

• chr19-10718246-G-T
• rs2068817566
• NM_001005361.3:c.4G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001005361.3(DNM2):​c.4G>T​(p.Gly2Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000753 in 1,328,298 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G2D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.5e-7 (0 hom.)
• Consequence: DNM2 NM_001005361.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.65
• 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.813

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNM2	NM_001005361.3	c.4G>T	p.Gly2Cys	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.4G>T	p.Gly2Cys	missense_variant	Exon 1 of 21	5	NM_001005361.3	ENSP00000373905.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.53e-7 AC: 1 AN: 1328298 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 655010

African (AFR) AF: 0.00 AC: 0 AN: 26768

American (AMR) AF: 0.00 AC: 0 AN: 27744

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23160

East Asian (EAS) AF: 0.00 AC: 0 AN: 27940

South Asian (SAS) AF: 0.00 AC: 0 AN: 72778

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45950

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3894

European-Non Finnish (NFE) AF: 9.56e-7 AC: 1 AN: 1045652

Other (OTH) AF: 0.00 AC: 0 AN: 54412

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	.;.;.;D;.
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.81	D;D;D;D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Uncertain	2.8	M;M;M;M;M
PhyloP100		8.7
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-3.9	.;D;D;D;D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0010	.;D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D
Polyphen		1.0	.;D;.;D;.
Vest4		0.52
MutPred		0.39		Loss of disorder (P = 0.0383);Loss of disorder (P = 0.0383);Loss of disorder (P = 0.0383);Loss of disorder (P = 0.0383);Loss of disorder (P = 0.0383);
MVP		0.94
MPC		2.2
ClinPred		1.0	D
GERP RS		5.0
PromoterAI		-0.060	Neutral
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.8
Varity_R		0.82
gMVP		0.86
Mutation Taster		=28/72	disease causing

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: rs2068817566; hg19: chr19-10828922;