dbSNP rs147026993: DNM2:c.235+12C>A (chr19-10759823-C-A) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001005361.3(DNM2):c.235+12C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0126 in 1,613,952 control chromosomes in the GnomAD database, including 173 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0093 ( 11 hom., cov: 31)

Exomes 𝑓: 0.013 ( 162 hom. )

Consequence

DNM2
NM_001005361.3 intron

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:10

Conservation

PhyloP100: -1.87

Publications

1 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:

LOC124904637 (HGNC:):

LOC124904637 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

BP6

Variant 19-10759823-C-A is Benign according to our data. Variant chr19-10759823-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 158524.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00932 (1419/152184) while in subpopulation NFE AF = 0.0144 (979/67996). AF 95% confidence interval is 0.0136. There are 11 homozygotes in GnomAd4. There are 672 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 11 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.235+12C>A	intron	N/A	NP_001005361.1	P50570-4
DNM2	NM_001005360.3		c.235+12C>A	intron	N/A	NP_001005360.1	P50570-1
DNM2	NM_001190716.2		c.235+12C>A	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.235+12C>A	intron	N/A	ENSP00000373905.4	P50570-4
DNM2	ENST00000355667.11	TSL:1	c.235+12C>A	intron	N/A	ENSP00000347890.6	P50570-1
DNM2	ENST00000585892.5	TSL:1	c.235+12C>A	intron	N/A	ENSP00000468734.1	P50570-5

Frequencies

GnomAD3 genomes

AF:

0.00932

AC:

1418

AN:

152066

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00304

Gnomad AMI

AF:

0.00661

Gnomad AMR

AF:

0.00262

Gnomad ASJ

AF:

0.00662

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00623

Gnomad FIN

AF:

0.0186

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0144

Gnomad OTH

AF:

0.00768

GnomAD2 exomes

AF:

0.0105

AC:

2630

AN:

251440

AF XY:

0.0103

show subpopulations

Gnomad AFR exome

AF:

0.00265

Gnomad AMR exome

AF:

0.00341

Gnomad ASJ exome

AF:

0.00546

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0220

Gnomad NFE exome

AF:

0.0147

Gnomad OTH exome

AF:

0.00929

GnomAD4 exome

AF:

0.0130

AC:

18995

AN:

1461768

Hom.:

162

Cov.:

AF XY:

0.0127

AC XY:

9257

AN XY:

727190

show subpopulations

African (AFR)

AF:

0.00182

AC:

AN:

33480

American (AMR)

AF:

0.00344

AC:

154

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00528

AC:

138

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00737

AC:

636

AN:

86258

European-Finnish (FIN)

AF:

0.0220

AC:

1172

AN:

53386

Middle Eastern (MID)

AF:

0.00277

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0146

AC:

16218

AN:

1111926

Other (OTH)

AF:

0.00993

AC:

600

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.439

Heterozygous variant carriers

1104

2208

3313

4417

5521

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

590

1180

1770

2360

2950

<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:

0.00932

AC:

1419

AN:

152184

Hom.:

Cov.:

AF XY:

0.00903

AC XY:

672

AN XY:

74402

show subpopulations

African (AFR)

AF:

0.00303

AC:

126

AN:

41530

American (AMR)

AF:

0.00262

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00662

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5180

South Asian (SAS)

AF:

0.00644

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.0186

AC:

197

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0144

AC:

979

AN:

67996

Other (OTH)

AF:

0.00760

AC:

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

150

225

300

375

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:

0.00689

Hom.:

Bravo

AF:

0.00793

Asia WGS

AF:

0.00231

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (4)

not provided (3)

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

Autosomal dominant centronuclear myopathy (1)

Centronuclear myopathy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

0.078

(source)

DANN

Benign

0.49

PhyloP100

-1.9

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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