rs147668465

Variant names:

• chr19-10797401-C-T
• rs147668465
• NM_001005361.3:c.1218C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001005361.3(DNM2):​c.1218C>T​(p.Asp406Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00196 in 1,613,356 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0014 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0020 (15 hom.)
• Consequence: DNM2 NM_001005361.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 3.40
• 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: 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

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BP6: Variant 19-10797401-C-T is Benign according to our data. Variant chr19-10797401-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 382721.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=3.4 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00142 (216/152278) while in subpopulation SAS AF = 0.00748 (36/4816). AF 95% confidence interval is 0.00555. There are 1 homozygotes in GnomAd4. There are 118 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 15 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.1218C>T	p.Asp406Asp	synonymous	Exon 10 of 21	NP_001005361.1	P50570-4
	DNM2	NM_001005362.3		c.1218C>T	p.Asp406Asp	synonymous	Exon 10 of 20	NP_001005362.1	P50570-3
	DNM2	NM_001005360.3		c.1336-1085C>T		intron	N/A	NP_001005360.1	P50570-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNM2	ENST00000389253.9	TSL:5 MANE Select	c.1218C>T	p.Asp406Asp	synonymous	Exon 10 of 21	ENSP00000373905.4	P50570-4
	DNM2	ENST00000355667.11	TSL:1	c.1336-1085C>T		intron	N/A	ENSP00000347890.6	P50570-1
	DNM2	ENST00000585892.5	TSL:1	c.1336-1085C>T		intron	N/A	ENSP00000468734.1	P50570-5

Frequencies

GnomAD3 genomes AF: 0.00142 AC: 216 AN: 152160 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00138

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00747

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00203

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.00190 AC: 477 AN: 251198 AF XY: 0.00231

Gnomad AFR exome AF: 0.000370

Gnomad AMR exome AF: 0.000666

Gnomad ASJ exome AF: 0.00198

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000232

Gnomad NFE exome AF: 0.00191

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.00201 AC: 2940 AN: 1461078 Hom.: 15 Cov.: 32 AF XY: 0.00218 AC XY: 1586 AN XY: 726824

African (AFR) AF: 0.000269 AC: 9 AN: 33460

American (AMR) AF: 0.000649 AC: 29 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00249 AC: 65 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00715 AC: 616 AN: 86206

European-Finnish (FIN) AF: 0.000675 AC: 36 AN: 53294

Middle Eastern (MID) AF: 0.00344 AC: 18 AN: 5232

European-Non Finnish (NFE) AF: 0.00183 AC: 2037 AN: 1111996

Other (OTH) AF: 0.00215 AC: 130 AN: 60338

GnomAD4 genome AF: 0.00142 AC: 216 AN: 152278 Hom.: 1 Cov.: 31 AF XY: 0.00158 AC XY: 118 AN XY: 74460

African (AFR) AF: 0.000241 AC: 10 AN: 41550

American (AMR) AF: 0.00137 AC: 21 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00748 AC: 36 AN: 4816

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

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00203 AC: 138 AN: 68042

Other (OTH) AF: 0.000474 AC: 1 AN: 2108

Alfa AF: 0.00131 Hom.: 0

Bravo AF: 0.00125

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.00224

EpiControl AF: 0.00326

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
CADD	Benign	11
DANN	Benign	0.55
PhyloP100		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

dbSNP: rs147668465; hg19: chr19-10908077;