rs879254300

Variant names:

• chr19-10829253-G-A
• rs879254300
• NM_001005361.3:c.2276G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_001005361.3(DNM2):​c.2276G>A​(p.Ser759Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000242 in 1,613,264 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S759S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: DNM2 NM_001005361.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.0260

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]

MIR6793 (HGNC:50251): (microRNA 6793) 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.04726538).
• BP6: Variant 19-10829253-G-A is Benign according to our data. Variant chr19-10829253-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 246533.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNM2	NM_001005361.3	c.2276G>A	p.Ser759Asn	missense_variant	Exon 19 of 21	ENST00000389253.9	NP_001005361.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNM2	ENST00000389253.9	c.2276G>A	p.Ser759Asn	missense_variant	Exon 19 of 21	5	NM_001005361.3	ENSP00000373905.4

Frequencies

GnomAD3 genomes AF: 0.0000328 AC: 5 AN: 152238 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

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: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000401 AC: 1 AN: 249292 AF XY: 0.00000740

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000233 AC: 34 AN: 1461026 Hom.: 0 Cov.: 33 AF XY: 0.0000261 AC XY: 19 AN XY: 726868

Gnomad4 AFR exome AF: 0.0000299 AC: 1 AN: 33470

Gnomad4 AMR exome AF: 0.0000224 AC: 1 AN: 44716

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26134

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39700

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 86254

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 52694

Gnomad4 NFE exome AF: 0.0000288 AC: 32 AN: 1111946

Gnomad4 Remaining exome AF: 0.00 AC: 0 AN: 60346

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152238 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74372

Gnomad4 AFR AF: 0.0000241 AC: 0.0000241255 AN: 0.0000241255

Gnomad4 AMR AF: 0.00 AC: 0 AN: 0

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.0000588 AC: 0.000058782 AN: 0.000058782

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000302

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Apr 07, 2016

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The S759N variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. However, the S759N variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Additionally, this substitution occurs at a position that is not conserved, and in silico analysis predicts this variant likely does not alter the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

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

Dec 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	1.9
DANN	Benign	0.83
DEOGEN2	Benign	0.41	.;.;.;T;.
Eigen	Benign	-0.99
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.097	N
LIST_S2	Benign	0.61	T;T;T;T;T
M_CAP	Benign	0.064	D
MetaRNN	Benign	0.047	T;T;T;T;T
MetaSVM	Benign	-0.55	T
MutationAssessor	Benign	0.49	N;.;N;N;.
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.030	.;.;N;.;N
REVEL	Benign	0.080
Sift	Benign	0.51	.;.;T;.;T
Sift4G	Benign	0.51	T;T;T;T;T
Polyphen		0.0	.;B;.;B;.
Vest4		0.035
MutPred		0.24		Loss of glycosylation at S759 (P = 0.0078);.;Loss of glycosylation at S759 (P = 0.0078);Loss of glycosylation at S759 (P = 0.0078);.;
MVP		0.46
MPC		0.28
ClinPred		0.040	T
GERP RS		-1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.016
gMVP		0.10
Mutation Taster		=96/4	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

Publications

LitVar

Other links and lift over

dbSNP: rs879254300; hg19: chr19-10939929;