19-10759766-G-T

Variant names:

• chr19-10759766-G-T
• rs144250390
• NM_001005361.3:c.190G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001005361.3(DNM2):​c.190G>T​(p.Val64Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,868 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V64I) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DNM2 NM_001005361.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.17
• Publications: 0 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

LOC124904637 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.98

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.190G>T	p.Val64Phe	missense	Exon 2 of 21	NP_001005361.1
	DNM2	NM_001005360.3		c.190G>T	p.Val64Phe	missense	Exon 2 of 21	NP_001005360.1
	DNM2	NM_001190716.2		c.190G>T	p.Val64Phe	missense	Exon 2 of 21	NP_001177645.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNM2	ENST00000389253.9	TSL:5 MANE Select	c.190G>T	p.Val64Phe	missense	Exon 2 of 21	ENSP00000373905.4
	DNM2	ENST00000355667.11	TSL:1	c.190G>T	p.Val64Phe	missense	Exon 2 of 21	ENSP00000347890.6
	DNM2	ENST00000585892.5	TSL:1	c.190G>T	p.Val64Phe	missense	Exon 2 of 21	ENSP00000468734.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461868 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727240

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

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

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

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.41	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.1	H
PhyloP100		6.2
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-4.4	D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.012	D
Polyphen		0.98	D
Vest4		0.90
MutPred		0.93		Loss of catalytic residue at V64 (P = 0.1677)
MVP		0.97
MPC		2.5
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.84
gMVP		0.92
Mutation Taster		=42/58	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: rs144250390; hg19: chr19-10870442;