rs201979143

Variant names:

• chr19-10830385-C-G
• rs201979143
• NM_001005361.3:c.2543+7C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001005361.3(DNM2):​c.2543+7C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00475 in 1,606,916 control chromosomes in the GnomAD database, including 36 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0035 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0049 (35 hom.)
• Consequence: DNM2 NM_001005361.3 splice_region, intron
• Scores: Splicing: ADA: 0.00004586
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -1.95
• Publications: 2 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 19-10830385-C-G is Benign according to our data. Variant chr19-10830385-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 158527.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 = 0.00346 (527/152276) while in subpopulation NFE AF = 0.00497 (338/68006). AF 95% confidence interval is 0.00453. There are 1 homozygotes in GnomAd4. There are 269 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 35 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNM2	NM_001005361.3	MANE Select	c.2543+7C>G		splice_region intron	N/A	NP_001005361.1
	DNM2	NM_001005360.3		c.2543+7C>G		splice_region intron	N/A	NP_001005360.1
	DNM2	NM_001190716.2		c.2543+7C>G		splice_region intron	N/A	NP_001177645.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNM2	ENST00000389253.9	TSL:5 MANE Select	c.2543+7C>G		splice_region intron	N/A	ENSP00000373905.4
	DNM2	ENST00000355667.11	TSL:1	c.2543+7C>G		splice_region intron	N/A	ENSP00000347890.6
	DNM2	ENST00000585892.5	TSL:1	c.2543+7C>G		splice_region intron	N/A	ENSP00000468734.1

Frequencies

GnomAD3 genomes AF: 0.00346 AC: 527 AN: 152158 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000917

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00412

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00565

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00497

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00361 AC: 877 AN: 243226 AF XY: 0.00364

Gnomad AFR exome AF: 0.00114

Gnomad AMR exome AF: 0.00354

Gnomad ASJ exome AF: 0.00696

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00452

Gnomad NFE exome AF: 0.00493

Gnomad OTH exome AF: 0.00531

GnomAD4 exome AF: 0.00489 AC: 7112 AN: 1454640 Hom.: 35 Cov.: 32 AF XY: 0.00474 AC XY: 3433 AN XY: 723916

African (AFR) AF: 0.000956 AC: 32 AN: 33460

American (AMR) AF: 0.00347 AC: 155 AN: 44648

Ashkenazi Jewish (ASJ) AF: 0.00587 AC: 153 AN: 26052

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.000661 AC: 57 AN: 86208

European-Finnish (FIN) AF: 0.00471 AC: 226 AN: 47940

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5752

European-Non Finnish (NFE) AF: 0.00558 AC: 6194 AN: 1110612

Other (OTH) AF: 0.00488 AC: 294 AN: 60286

GnomAD4 genome AF: 0.00346 AC: 527 AN: 152276 Hom.: 1 Cov.: 32 AF XY: 0.00361 AC XY: 269 AN XY: 74452

African (AFR) AF: 0.000914 AC: 38 AN: 41556

American (AMR) AF: 0.00412 AC: 63 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00490 AC: 17 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4832

European-Finnish (FIN) AF: 0.00565 AC: 60 AN: 10618

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

European-Non Finnish (NFE) AF: 0.00497 AC: 338 AN: 68006

Other (OTH) AF: 0.00378 AC: 8 AN: 2114

Alfa AF: 0.00492 Hom.: 0

Bravo AF: 0.00339

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00523

EpiControl AF: 0.00380

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	2	Charcot-Marie-Tooth disease dominant intermediate B (2)
-	-	2	not specified (2)
-	-	1	Autosomal dominant centronuclear myopathy (1)
-	-	1	Charcot-Marie-Tooth disease dominant intermediate B;C4551952:Autosomal dominant centronuclear myopathy;C4706410:Fetal akinesia-cerebral and retinal hemorrhage syndrome (1)
-	-	1	DNM2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.81
DANN	Benign	0.55
PhyloP100		-2.0
PromoterAI		-0.039	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000046
dbscSNV1_RF	Benign	0.010
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: rs201979143; hg19: chr19-10941061;