2-219420460-C-A

Variant names:

Variant summary

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

The NM_001927.4(DES):c.736-35C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0419 in 1,613,716 control chromosomes in the GnomAD database, including 1,612 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.034 ( 126 hom., cov: 32)

Exomes 𝑓: 0.043 ( 1486 hom. )

Consequence

DES
NM_001927.4 intron

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.0820

Publications

5 publications found

Variant links:

Genes affected

DES (HGNC:2770): (desmin) This gene encodes a muscle-specific class III intermediate filament. Homopolymers of this protein form a stable intracytoplasmic filamentous network connecting myofibrils to each other and to the plasma membrane. Mutations in this gene are associated with desmin-related myopathy, a familial cardiac and skeletal myopathy (CSM), and with distal myopathies. [provided by RefSeq, Jul 2008]

DES Gene-Disease associations (from GenCC):

dilated cardiomyopathy
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
dilated cardiomyopathy 1I
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
myofibrillar myopathy 1
Inheritance: AD, AR, SD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
atrioventricular block
Inheritance: AD, AR Classification: STRONG Submitted by: Genomics England PanelApp
arrhythmogenic right ventricular cardiomyopathy
Inheritance: AD Classification: MODERATE Submitted by: ClinGen
familial isolated dilated cardiomyopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
neurogenic scapuloperoneal syndrome, Kaeser type
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

DES links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.62).

BP6

Variant 2-219420460-C-A is Benign according to our data. Variant chr2-219420460-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 258492.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 = 0.0336 (5115/152122) while in subpopulation NFE AF = 0.0498 (3385/67982). AF 95% confidence interval is 0.0484. There are 126 homozygotes in GnomAd4. There are 2437 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 126 AD,AR,SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DES	NM_001927.4 link	c.736-35C>A		intron_variant	Intron 3 of 8	ENST00000373960.4	NP_001918.3	P17661Q53SB5

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
DES	ENST00000373960.4 link	c.736-35C>A	intron_variant	Intron 3 of 8	1	NM_001927.4	ENSP00000363071.3	P17661
DES	ENST00000477226.6 link	n.210-35C>A	intron_variant	Intron 2 of 7	4
DES	ENST00000492726.1 link	n.131-35C>A	intron_variant	Intron 2 of 5	4
DES	ENST00000683013.1 link	n.124-35C>A	intron_variant	Intron 1 of 6

Frequencies

GnomAD3 genomes

AF:

0.0337

AC:

5115

AN:

152004

Hom.:

126

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00829

Gnomad AMI

AF:

0.143

Gnomad AMR

AF:

0.0209

Gnomad ASJ

AF:

0.0579

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0205

Gnomad FIN

AF:

0.0540

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.0498

Gnomad OTH

AF:

0.0268

GnomAD2 exomes

AF:

0.0355

AC:

8877

AN:

250162

AF XY:

0.0362

show subpopulations

Gnomad AFR exome

AF:

0.00700

Gnomad AMR exome

AF:

0.0162

Gnomad ASJ exome

AF:

0.0612

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0495

Gnomad NFE exome

AF:

0.0495

Gnomad OTH exome

AF:

0.0373

GnomAD4 exome

AF:

0.0428

AC:

62566

AN:

1461594

Hom.:

1486

Cov.:

AF XY:

0.0426

AC XY:

30958

AN XY:

727084

show subpopulations

African (AFR)

AF:

0.00771

AC:

258

AN:

33478

American (AMR)

AF:

0.0177

AC:

790

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.0627

AC:

1638

AN:

26134

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39696

South Asian (SAS)

AF:

0.0239

AC:

2065

AN:

86228

European-Finnish (FIN)

AF:

0.0495

AC:

2638

AN:

53334

Middle Eastern (MID)

AF:

0.0505

AC:

291

AN:

5762

European-Non Finnish (NFE)

AF:

0.0473

AC:

52590

AN:

1111870

Other (OTH)

AF:

0.0380

AC:

2294

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

3524

7047

10571

14094

17618

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1910

3820

5730

7640

9550

<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:

0.0336

AC:

5115

AN:

152122

Hom.:

126

Cov.:

AF XY:

0.0328

AC XY:

2437

AN XY:

74348

show subpopulations

African (AFR)

AF:

0.00826

AC:

343

AN:

41506

American (AMR)

AF:

0.0210

AC:

321

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.0579

AC:

201

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5158

South Asian (SAS)

AF:

0.0208

AC:

100

AN:

4816

European-Finnish (FIN)

AF:

0.0540

AC:

572

AN:

10594

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0498

AC:

3385

AN:

67982

Other (OTH)

AF:

0.0266

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

247

495

742

990

1237

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

192

256

320

<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:

0.0429

Hom.:

Bravo

AF:

0.0304

Asia WGS

AF:

0.00693

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:2

Jun 15, 2018

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.62

CADD

Benign

9.2

(source)

DANN

Benign

0.84

PhyloP100

-0.082

Mutation Taster

=100/0

polymorphism (auto)

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over