Genetic Variant DNM2:c.1782-11C>T (chr19-10823777-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001005361.3(DNM2):c.1782-11C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00158 in 1,604,020 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). The gene DNM2 is included in the ClinGen Criteria Specification Registry.

Frequency

Genomes: 𝑓 0.0085 ( 22 hom., cov: 31)

Exomes 𝑓: 0.00085 ( 17 hom. )

Consequence

DNM2
NM_001005361.3 intron

Scores

Splicing: ADA: 0.0002264

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.0670

Publications

0 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

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

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant 19-10823777-C-T is Benign according to our data. Variant chr19-10823777-C-T is described in ClinVar as Benign. ClinVar VariationId is 158517.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0085 (1292/152086) while in subpopulation AFR AF = 0.0299 (1238/41470). AF 95% confidence interval is 0.0285. There are 22 homozygotes in GnomAd4. There are 613 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 22 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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
DNM2	NM_001005361.3	MANE Select	c.1782-11C>T	intron	N/A	NP_001005361.1	P50570-4
DNM2	NM_001005360.3		c.1782-11C>T	intron	N/A	NP_001005360.1	P50570-1
DNM2	NM_001190716.2		c.1782-11C>T	intron	N/A	NP_001177645.1	P50570-5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
DNM2	ENST00000389253.9	TSL:5 MANE Select	c.1782-11C>T	intron	N/A	ENSP00000373905.4	P50570-4
DNM2	ENST00000355667.11	TSL:1	c.1782-11C>T	intron	N/A	ENSP00000347890.6	P50570-1
DNM2	ENST00000585892.5	TSL:1	c.1782-11C>T	intron	N/A	ENSP00000468734.1	P50570-5

Frequencies

GnomAD3 genomes

AF:

0.00850

AC:

1291

AN:

151968

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0299

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00262

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:

0.0000441

Gnomad OTH

AF:

0.00526

GnomAD2 exomes

AF:

0.00220

AC:

548

AN:

248738

AF XY:

0.00161

show subpopulations

Gnomad AFR exome

AF:

0.0314

Gnomad AMR exome

AF:

0.00110

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000268

Gnomad OTH exome

AF:

0.000986

GnomAD4 exome

AF:

0.000854

AC:

1240

AN:

1451934

Hom.:

Cov.:

AF XY:

0.000794

AC XY:

574

AN XY:

722568

show subpopulations

African (AFR)

AF:

0.0318

AC:

1058

AN:

33288

American (AMR)

AF:

0.00125

AC:

AN:

44640

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25994

East Asian (EAS)

AF:

0.00

AC:

AN:

39500

South Asian (SAS)

AF:

0.0000349

AC:

AN:

86054

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52884

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00000544

AC:

AN:

1103882

Other (OTH)

AF:

0.00192

AC:

115

AN:

59932

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.549

Heterozygous variant carriers

139

209

278

348

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

102

136

170

<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:

0.00850

AC:

1292

AN:

152086

Hom.:

Cov.:

AF XY:

0.00824

AC XY:

613

AN XY:

74358

show subpopulations

African (AFR)

AF:

0.0299

AC:

1238

AN:

41470

American (AMR)

AF:

0.00262

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5162

South Asian (SAS)

AF:

0.00

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

67972

Other (OTH)

AF:

0.00520

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

127

190

254

317

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00586

Hom.:

Bravo

AF:

0.00953

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance: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)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

1.6

(source)

DANN

Benign

0.46

PhyloP100

0.067

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00023

dbscSNV1_RF

Benign

0.0

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