rs201575500

Variant names:

• chr19-10798534-A-G
• rs201575500
• NM_001005361.3:c.1384A>G

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS1

The NM_001005361.3(DNM2):​c.1384A>G​(p.Thr462Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000141 in 1,613,852 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T462I) has been classified as Uncertain significance. The gene DNM2 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: DNM2 NM_001005361.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:5
• Conservation: PhyloP100: 4.96
• 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

Specifications for DNM2 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.220121).
• BP6: Variant 19-10798534-A-G is Benign according to our data. Variant chr19-10798534-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 327980.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000151 (23/151974) while in subpopulation SAS AF = 0.00145 (7/4812). AF 95% confidence interval is 0.000683. There are 0 homozygotes in GnomAd4. There are 13 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

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.1384A>G	p.Thr462Ala	missense	Exon 11 of 21	NP_001005361.1	P50570-4
	DNM2	NM_001005360.3		c.1384A>G	p.Thr462Ala	missense	Exon 11 of 21	NP_001005360.1	P50570-1
	DNM2	NM_001190716.2		c.1384A>G	p.Thr462Ala	missense	Exon 11 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.1384A>G	p.Thr462Ala	missense	Exon 11 of 21	ENSP00000373905.4	P50570-4
	DNM2	ENST00000355667.11	TSL:1	c.1384A>G	p.Thr462Ala	missense	Exon 11 of 21	ENSP00000347890.6	P50570-1
	DNM2	ENST00000585892.5	TSL:1	c.1384A>G	p.Thr462Ala	missense	Exon 11 of 21	ENSP00000468734.1	P50570-5

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 151854 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000484

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000231 AC: 58 AN: 251428 AF XY: 0.000331

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000264

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000140 AC: 205 AN: 1461878 Hom.: 0 Cov.: 32 AF XY: 0.000165 AC XY: 120 AN XY: 727240

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.000246 AC: 11 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000359 AC: 31 AN: 86258

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53420

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.000130 AC: 145 AN: 1111998

Other (OTH) AF: 0.000199 AC: 12 AN: 60396

GnomAD4 genome AF: 0.000151 AC: 23 AN: 151974 Hom.: 0 Cov.: 31 AF XY: 0.000175 AC XY: 13 AN XY: 74278

African (AFR) AF: 0.0000483 AC: 2 AN: 41428

American (AMR) AF: 0.000131 AC: 2 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5146

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10588

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

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 67946

Other (OTH) AF: 0.00142 AC: 3 AN: 2108

Alfa AF: 0.000196 Hom.: 0

Bravo AF: 0.000110

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.000222 AC: 27

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.000652

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.86	D
Eigen	Benign	0.15
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.47	T
MutationAssessor	Benign	1.9	L
PhyloP100		5.0
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.33
Sift	Benign	0.091	T
Sift4G	Benign	0.51	T
Polyphen		0.088	B
Vest4		0.68
MVP		0.72
MPC		1.1
ClinPred		0.084	T
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.33
gMVP		0.75
Mutation Taster		=40/60	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: rs201575500; hg19: chr19-10909210;