19-10806008-C-T

Variant names:

• chr19-10806008-C-T
• rs2287029
• NM_001005361.3:c.1545+41C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001005361.3(DNM2):​c.1545+41C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.168 in 1,613,244 control chromosomes in the GnomAD database, including 24,287 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1613 hom., cov: 32)
  • Exomes 𝑓: 0.17 (22674 hom.)
• Consequence: DNM2 NM_001005361.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -3.79
• Publications: 16 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: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, Orphanet
• 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: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• hereditary spastic paraplegia

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 19-10806008-C-T is Benign according to our data. Variant chr19-10806008-C-T is described in ClinVar as Benign. ClinVar VariationId is 256865.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.174 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNM2	NM_001005361.3	MANE Select	c.1545+41C>T		intron	N/A	NP_001005361.1	P50570-4
	DNM2	NM_001005360.3		c.1545+41C>T		intron	N/A	NP_001005360.1	P50570-1
	DNM2	NM_001190716.2		c.1545+41C>T		intron	N/A	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.1545+41C>T		intron	N/A	ENSP00000373905.4	P50570-4
	DNM2	ENST00000355667.11	TSL:1	c.1545+41C>T		intron	N/A	ENSP00000347890.6	P50570-1
	DNM2	ENST00000585892.5	TSL:1	c.1545+41C>T		intron	N/A	ENSP00000468734.1	P50570-5

Frequencies

GnomAD3 genomes AF: 0.130 AC: 19810 AN: 152070 Hom.: 1613 Cov.: 32

Gnomad AFR AF: 0.0367

Gnomad AMI AF: 0.261

Gnomad AMR AF: 0.123

Gnomad ASJ AF: 0.199

Gnomad EAS AF: 0.168

Gnomad SAS AF: 0.127

Gnomad FIN AF: 0.155

Gnomad MID AF: 0.225

Gnomad NFE AF: 0.177

Gnomad OTH AF: 0.132

GnomAD2 exomes AF: 0.147 AC: 36851 AN: 250128 AF XY: 0.151

Gnomad AFR exome AF: 0.0353

Gnomad AMR exome AF: 0.0900

Gnomad ASJ exome AF: 0.204

Gnomad EAS exome AF: 0.154

Gnomad FIN exome AF: 0.141

Gnomad NFE exome AF: 0.176

Gnomad OTH exome AF: 0.165

GnomAD4 exome AF: 0.172 AC: 251988 AN: 1461056 Hom.: 22674 Cov.: 32 AF XY: 0.172 AC XY: 125123 AN XY: 726856

African (AFR) AF: 0.0320 AC: 1070 AN: 33474

American (AMR) AF: 0.0908 AC: 4057 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.202 AC: 5272 AN: 26128

East Asian (EAS) AF: 0.164 AC: 6524 AN: 39686

South Asian (SAS) AF: 0.145 AC: 12531 AN: 86240

European-Finnish (FIN) AF: 0.138 AC: 7334 AN: 53170

Middle Eastern (MID) AF: 0.219 AC: 1264 AN: 5766

European-Non Finnish (NFE) AF: 0.184 AC: 204239 AN: 1111520

Other (OTH) AF: 0.161 AC: 9697 AN: 60368

GnomAD4 genome AF: 0.130 AC: 19807 AN: 152188 Hom.: 1613 Cov.: 32 AF XY: 0.132 AC XY: 9807 AN XY: 74392

African (AFR) AF: 0.0366 AC: 1521 AN: 41556

American (AMR) AF: 0.123 AC: 1874 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.199 AC: 689 AN: 3470

East Asian (EAS) AF: 0.169 AC: 872 AN: 5174

South Asian (SAS) AF: 0.127 AC: 611 AN: 4824

European-Finnish (FIN) AF: 0.155 AC: 1646 AN: 10600

Middle Eastern (MID) AF: 0.221 AC: 65 AN: 294

European-Non Finnish (NFE) AF: 0.177 AC: 12010 AN: 67976

Other (OTH) AF: 0.134 AC: 282 AN: 2108

Alfa AF: 0.160 Hom.: 5876

Bravo AF: 0.125

Asia WGS AF: 0.123 AC: 431 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.050
DANN	Benign	0.71
PhyloP100		-3.8
RBP_binding_hub_radar		0.67
RBP_regulation_power_radar		3.2
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: rs2287029; hg19: chr19-10916684; COSMIC: COSV58958640; COSMIC: COSV58958640;