chr19-10777086-G-GCCTCTGA

Variant names:

• chr19-10777086-G-GCCTCTGA
• rs748362325
• NM_001005361.3:c.590-18_590-12dupACCTCTG

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_001005361.3(DNM2):​c.590-18_590-12dupACCTCTG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0022 in 1,611,150 control chromosomes in the GnomAD database, including 5 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (5 hom.)
• Consequence: DNM2 NM_001005361.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.450
• 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

ACMG classification

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

• BP6: Variant 19-10777086-G-GCCTCTGA is Benign according to our data. Variant chr19-10777086-G-GCCTCTGA is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 210855.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 = 0.00202 (307/152300) while in subpopulation NFE AF = 0.00315 (214/68034). AF 95% confidence interval is 0.0028. There are 0 homozygotes in GnomAd4. There are 137 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 5 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNM2	NM_001005361.3	MANE Select	c.590-18_590-12dupACCTCTG		intron	N/A	NP_001005361.1
	DNM2	NM_001005360.3		c.590-18_590-12dupACCTCTG		intron	N/A	NP_001005360.1
	DNM2	NM_001190716.2		c.590-18_590-12dupACCTCTG		intron	N/A	NP_001177645.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNM2	ENST00000389253.9	TSL:5 MANE Select	c.590-32_590-31insCCTCTGA		intron	N/A	ENSP00000373905.4
	DNM2	ENST00000355667.11	TSL:1	c.590-32_590-31insCCTCTGA		intron	N/A	ENSP00000347890.6
	DNM2	ENST00000585892.5	TSL:1	c.590-32_590-31insCCTCTGA		intron	N/A	ENSP00000468734.1

Frequencies

GnomAD3 genomes AF: 0.00202 AC: 307 AN: 152182 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000434

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00268

Gnomad ASJ AF: 0.00606

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00315

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00211 AC: 530 AN: 251140 AF XY: 0.00211

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.00237

Gnomad ASJ exome AF: 0.00516

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.000925

Gnomad NFE exome AF: 0.00280

Gnomad OTH exome AF: 0.00310

GnomAD4 exome AF: 0.00222 AC: 3232 AN: 1458850 Hom.: 5 Cov.: 30 AF XY: 0.00218 AC XY: 1579 AN XY: 725866

African (AFR) AF: 0.000479 AC: 16 AN: 33404

American (AMR) AF: 0.00246 AC: 110 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00555 AC: 145 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39666

South Asian (SAS) AF: 0.000986 AC: 85 AN: 86182

European-Finnish (FIN) AF: 0.000806 AC: 43 AN: 53382

Middle Eastern (MID) AF: 0.00434 AC: 25 AN: 5754

European-Non Finnish (NFE) AF: 0.00239 AC: 2651 AN: 1109352

Other (OTH) AF: 0.00260 AC: 157 AN: 60288

GnomAD4 genome AF: 0.00202 AC: 307 AN: 152300 Hom.: 0 Cov.: 32 AF XY: 0.00184 AC XY: 137 AN XY: 74478

African (AFR) AF: 0.000433 AC: 18 AN: 41558

American (AMR) AF: 0.00268 AC: 41 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00606 AC: 21 AN: 3466

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4826

European-Finnish (FIN) AF: 0.000282 AC: 3 AN: 10626

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00315 AC: 214 AN: 68034

Other (OTH) AF: 0.00284 AC: 6 AN: 2112

Alfa AF: 0.00334 Hom.: 0

Bravo AF: 0.00194

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Jan 08, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.45
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs748362325; hg19: chr19-10887762;