19-10775530-G-T

Variant names:

• chr19-10775530-G-T
• rs4804528
• NM_001005361.3:c.386-173G>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001005361.3(DNM2):​c.386-173G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.322 in 152,040 control chromosomes in the GnomAD database, including 8,952 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.32 (8952 hom., cov: 32)
• Consequence: DNM2 NM_001005361.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.335
• Publications: 18 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]

DNM2 Gene-Disease associations (from GenCC):

• autosomal dominant centronuclear myopathy

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: ClinGen, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Charcot-Marie-Tooth disease

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• Charcot-Marie-Tooth disease dominant intermediate B

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• autosomal dominant Charcot-Marie-Tooth disease type 2M

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• fetal akinesia-cerebral and retinal hemorrhage syndrome

  Inheritance: AR Classification: SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
• hereditary spastic paraplegia

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 19-10775530-G-T is Benign according to our data. Variant chr19-10775530-G-T is described in ClinVar as Benign. ClinVar VariationId is 679310.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.42 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNM2	NM_001005361.3	MANE Select	c.386-173G>T		intron	N/A	NP_001005361.1
	DNM2	NM_001005360.3		c.386-173G>T		intron	N/A	NP_001005360.1
	DNM2	NM_001190716.2		c.386-173G>T		intron	N/A	NP_001177645.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNM2	ENST00000389253.9	TSL:5 MANE Select	c.386-173G>T		intron	N/A	ENSP00000373905.4
	DNM2	ENST00000355667.11	TSL:1	c.386-173G>T		intron	N/A	ENSP00000347890.6
	DNM2	ENST00000585892.5	TSL:1	c.386-173G>T		intron	N/A	ENSP00000468734.1

Frequencies

GnomAD3 genomes AF: 0.322 AC: 48956 AN: 151922 Hom.: 8949 Cov.: 32

Gnomad AFR AF: 0.162

Gnomad AMI AF: 0.476

Gnomad AMR AF: 0.274

Gnomad ASJ AF: 0.436

Gnomad EAS AF: 0.204

Gnomad SAS AF: 0.308

Gnomad FIN AF: 0.370

Gnomad MID AF: 0.478

Gnomad NFE AF: 0.424

Gnomad OTH AF: 0.336

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.322 AC: 48969 AN: 152040 Hom.: 8952 Cov.: 32 AF XY: 0.318 AC XY: 23645 AN XY: 74298

African (AFR) AF: 0.162 AC: 6733 AN: 41490

American (AMR) AF: 0.273 AC: 4173 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.436 AC: 1513 AN: 3472

East Asian (EAS) AF: 0.205 AC: 1058 AN: 5164

South Asian (SAS) AF: 0.308 AC: 1488 AN: 4828

European-Finnish (FIN) AF: 0.370 AC: 3907 AN: 10550

Middle Eastern (MID) AF: 0.466 AC: 137 AN: 294

European-Non Finnish (NFE) AF: 0.424 AC: 28822 AN: 67960

Other (OTH) AF: 0.334 AC: 705 AN: 2110

Alfa AF: 0.389 Hom.: 39598

Bravo AF: 0.309

Asia WGS AF: 0.243 AC: 848 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 14, 2018

GeneDx

Significance: 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.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.38
DANN	Benign	0.42
PhyloP100		-0.34
Mutation Taster		=100/0	polymorphism (auto)

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: rs4804528; hg19: chr19-10886206;