rs2229919

Variant names:

• chr19-10825065-C-T
• rs2229919
• NM_001005361.3:c.1902C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001005361.3(DNM2):​c.1902C>T​(p.Asn634Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0025 in 1,614,110 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0026 (13 hom.)
• Consequence: DNM2 NM_001005361.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -1.87
• Publications: 4 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 19-10825065-C-T is Benign according to our data. Variant chr19-10825065-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 158521.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.87 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0014 (213/152266) while in subpopulation NFE AF = 0.00243 (165/68018). AF 95% confidence interval is 0.00212. There are 0 homozygotes in GnomAd4. There are 108 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 13 AD,AR gene

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.1902C>T	p.Asn634Asn	synonymous	Exon 18 of 21	NP_001005361.1	P50570-4
	DNM2	NM_001005360.3		c.1902C>T	p.Asn634Asn	synonymous	Exon 18 of 21	NP_001005360.1	P50570-1
	DNM2	NM_001190716.2		c.1902C>T	p.Asn634Asn	synonymous	Exon 18 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.1902C>T	p.Asn634Asn	synonymous	Exon 18 of 21	ENSP00000373905.4	P50570-4
	DNM2	ENST00000355667.11	TSL:1	c.1902C>T	p.Asn634Asn	synonymous	Exon 18 of 21	ENSP00000347890.6	P50570-1
	DNM2	ENST00000585892.5	TSL:1	c.1902C>T	p.Asn634Asn	synonymous	Exon 18 of 21	ENSP00000468734.1	P50570-5

Frequencies

GnomAD3 genomes AF: 0.00140 AC: 213 AN: 152150 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00243

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.00144 AC: 361 AN: 251102 AF XY: 0.00138

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.00130

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00256

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.00262 AC: 3823 AN: 1461844 Hom.: 13 Cov.: 31 AF XY: 0.00258 AC XY: 1874 AN XY: 727222

African (AFR) AF: 0.000418 AC: 14 AN: 33480

American (AMR) AF: 0.00130 AC: 58 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000301 AC: 26 AN: 86256

European-Finnish (FIN) AF: 0.000150 AC: 8 AN: 53414

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.00324 AC: 3603 AN: 1111988

Other (OTH) AF: 0.00184 AC: 111 AN: 60386

GnomAD4 genome AF: 0.00140 AC: 213 AN: 152266 Hom.: 0 Cov.: 32 AF XY: 0.00145 AC XY: 108 AN XY: 74448

African (AFR) AF: 0.000409 AC: 17 AN: 41560

American (AMR) AF: 0.00150 AC: 23 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4820

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00243 AC: 165 AN: 68018

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.00185 Hom.: 0

Bravo AF: 0.00138

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.00294

EpiControl AF: 0.00261

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	not provided (4)
-	-	2	Charcot-Marie-Tooth disease dominant intermediate B (2)
-	-	1	Autosomal dominant centronuclear myopathy (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	2.1
DANN	Benign	0.34
PhyloP100		-1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2229919; hg19: chr19-10935741; COSMIC: COSV58957828; COSMIC: COSV58957828;