19-10825136-A-G

Variant names:

• chr19-10825136-A-G
• rs753175954
• NM_001005361.3:c.1973A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PP3 BP6

The NM_001005361.3(DNM2):​c.1973A>G​(p.Asn658Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,614,124 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). The gene DNM2 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: DNM2 NM_001005361.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 9.23
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.84
• BP6: Variant 19-10825136-A-G is Benign according to our data. Variant chr19-10825136-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 210854.

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.1973A>G	p.Asn658Ser	missense	Exon 18 of 21	NP_001005361.1	P50570-4
	DNM2	NM_001005360.3		c.1973A>G	p.Asn658Ser	missense	Exon 18 of 21	NP_001005360.1	P50570-1
	DNM2	NM_001190716.2		c.1973A>G	p.Asn658Ser	missense	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.1973A>G	p.Asn658Ser	missense	Exon 18 of 21	ENSP00000373905.4	P50570-4
	DNM2	ENST00000355667.11	TSL:1	c.1973A>G	p.Asn658Ser	missense	Exon 18 of 21	ENSP00000347890.6	P50570-1
	DNM2	ENST00000585892.5	TSL:1	c.1973A>G	p.Asn658Ser	missense	Exon 18 of 21	ENSP00000468734.1	P50570-5

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152234 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461890 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727246

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000719 AC: 8 AN: 1112010

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152234 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74372

African (AFR) AF: 0.00 AC: 0 AN: 41466

American (AMR) AF: 0.00 AC: 0 AN: 15286

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68042

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Benign	-0.095	T
BayesDel_noAF	Benign	-0.37
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.53	D
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.034	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	1.8	L
PhyloP100		9.2
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Uncertain	0.35
Sift	Benign	0.10	T
Sift4G	Benign	0.19	T
Polyphen		1.0	D
Vest4		0.85
MutPred		0.60		Loss of stability (P = 0.0418)
MVP		0.82
MPC		1.7
ClinPred		0.99	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.38
gMVP		0.73
Mutation Taster		=44/56	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: rs753175954; hg19: chr19-10935812; COSMIC: COSV58958018; COSMIC: COSV58958018;