19-10772481-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS1

The NM_001005361.3(DNM2):c.238C>T(p.His80Tyr) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00186 in 1,614,112 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0019 ( 1 hom. )

Consequence

DNM2
NM_001005361.3 missense, splice_region

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 4.24

Publications

7 publications found

Variant links:

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

DNM2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011853009).

BP6

Variant 19-10772481-C-T is Benign according to our data. Variant chr19-10772481-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 137130.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00119 (182/152322) while in subpopulation NFE AF = 0.00213 (145/68040). AF 95% confidence interval is 0.00185. There are 0 homozygotes in GnomAd4. There are 79 alleles in the male GnomAd4 subpopulation. Median coverage is 32. 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DNM2	NM_001005361.3	MANE Select	c.238C>T	p.His80Tyr	missense splice_region	Exon 3 of 21	NP_001005361.1	P50570-4
DNM2	NM_001005360.3		c.238C>T	p.His80Tyr	missense splice_region	Exon 3 of 21	NP_001005360.1	P50570-1
DNM2	NM_001190716.2		c.238C>T	p.His80Tyr	missense splice_region	Exon 3 of 21	NP_001177645.1	P50570-5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DNM2	ENST00000389253.9	TSL:5 MANE Select	c.238C>T	p.His80Tyr	missense splice_region	Exon 3 of 21	ENSP00000373905.4	P50570-4
DNM2	ENST00000355667.11	TSL:1	c.238C>T	p.His80Tyr	missense splice_region	Exon 3 of 21	ENSP00000347890.6	P50570-1
DNM2	ENST00000585892.5	TSL:1	c.238C>T	p.His80Tyr	missense splice_region	Exon 3 of 21	ENSP00000468734.1	P50570-5

Frequencies

GnomAD3 genomes

AF:

0.00119

AC:

181

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.000753

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00213

Gnomad OTH

AF:

0.000956

GnomAD2 exomes

AF:

0.00108

AC:

272

AN:

251382

AF XY:

0.00121

show subpopulations

Gnomad AFR exome

AF:

0.000369

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000510

Gnomad NFE exome

AF:

0.00178

Gnomad OTH exome

AF:

0.00114

GnomAD4 exome

AF:

0.00193

AC:

2818

AN:

1461790

Hom.:

Cov.:

AF XY:

0.00189

AC XY:

1371

AN XY:

727204

show subpopulations

African (AFR)

AF:

0.000179

AC:

AN:

33480

American (AMR)

AF:

0.0000224

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00126

AC:

109

AN:

86256

European-Finnish (FIN)

AF:

0.000581

AC:

AN:

53358

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00227

AC:

2529

AN:

1111978

Other (OTH)

AF:

0.00235

AC:

142

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.438

Heterozygous variant carriers

149

298

447

596

745

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

196

294

392

490

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00119

AC:

182

AN:

152322

Hom.:

Cov.:

AF XY:

0.00106

AC XY:

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.000481

AC:

AN:

41570

American (AMR)

AF:

0.00

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00145

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.000753

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00213

AC:

145

AN:

68040

Other (OTH)

AF:

0.000946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00166

Hom.:

Bravo

AF:

0.00118

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00244

AC:

ExAC

AF:

0.000955

AC:

116

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00218

EpiControl

AF:

0.00207

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Charcot-Marie-Tooth disease dominant intermediate B (2)

not provided (2)

not specified (2)

Autosomal dominant centronuclear myopathy (1)

DNM2-related disorder (1)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.026

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.20

CADD

Benign

(source)

DANN

Benign

0.36

DEOGEN2

Uncertain

0.63

Eigen

Benign

-0.92

Eigen_PC

Benign

-0.59

FATHMM_MKL

Benign

0.39

LIST_S2

Benign

0.72

M_CAP

Benign

0.037

MetaRNN

Benign

0.012

MetaSVM

Benign

-0.37

MutationAssessor

Benign

-2.3

PhyloP100

4.2

PrimateAI

Uncertain

0.79

PROVEAN

Benign

4.2

REVEL

Benign

0.27

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.27

MVP

0.41

MPC

1.1

ClinPred

0.0021

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.018

gMVP

0.48

Mutation Taster

=100/0

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over