dbSNP rs1058284: DES:p.Ala368Ala (chr2-219421420-G-A) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001927.4(DES):c.1104G>A(p.Ala368Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.344 in 1,613,624 control chromosomes in the GnomAD database, including 97,240 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.36 ( 10366 hom., cov: 31)

Exomes 𝑓: 0.34 ( 86874 hom. )

Consequence

DES
NM_001927.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:19

Conservation

PhyloP100: -4.32

Publications

24 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
myofibrillar myopathy
Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen
myofibrillar myopathy 1
Inheritance: SD, AD, AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
atrioventricular block
Inheritance: AR, AD 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.98).

BP6

Variant 2-219421420-G-A is Benign according to our data. Variant chr2-219421420-G-A is described in ClinVar as Benign. ClinVar VariationId is 44245.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-4.32 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.429 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001927.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DES	NM_001927.4	MANE Select	c.1104G>A	p.Ala368Ala	synonymous	Exon 6 of 9	NP_001918.3
DES	NM_001382708.1		c.1101G>A	p.Ala367Ala	synonymous	Exon 6 of 9	NP_001369637.1
DES	NM_001382712.1		c.1104G>A	p.Ala368Ala	synonymous	Exon 6 of 9	NP_001369641.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DES	ENST00000373960.4	TSL:1 MANE Select	c.1104G>A	p.Ala368Ala	synonymous	Exon 6 of 9	ENSP00000363071.3	P17661
DES	ENST00000942906.1		c.1104G>A	p.Ala368Ala	synonymous	Exon 6 of 10	ENSP00000612965.1
DES	ENST00000942898.1		c.1104G>A	p.Ala368Ala	synonymous	Exon 6 of 9	ENSP00000612957.1

Frequencies

GnomAD3 genomes

AF:

0.363

AC:

55087

AN:

151706

Hom.:

10347

Cov.:

show subpopulations

Gnomad AFR

AF:

0.435

Gnomad AMI

AF:

0.436

Gnomad AMR

AF:

0.365

Gnomad ASJ

AF:

0.412

Gnomad EAS

AF:

0.185

Gnomad SAS

AF:

0.296

Gnomad FIN

AF:

0.265

Gnomad MID

AF:

0.418

Gnomad NFE

AF:

0.348

Gnomad OTH

AF:

0.382

GnomAD2 exomes

AF:

0.332

AC:

83512

AN:

251348

AF XY:

0.333

show subpopulations

Gnomad AFR exome

AF:

0.440

Gnomad AMR exome

AF:

0.310

Gnomad ASJ exome

AF:

0.421

Gnomad EAS exome

AF:

0.190

Gnomad FIN exome

AF:

0.280

Gnomad NFE exome

AF:

0.357

Gnomad OTH exome

AF:

0.359

GnomAD4 exome

AF:

0.342

AC:

499613

AN:

1461800

Hom.:

86874

Cov.:

AF XY:

0.341

AC XY:

247839

AN XY:

727212

show subpopulations

African (AFR)

AF:

0.440

AC:

14720

AN:

33480

American (AMR)

AF:

0.316

AC:

14128

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.415

AC:

10856

AN:

26136

East Asian (EAS)

AF:

0.183

AC:

7283

AN:

39700

South Asian (SAS)

AF:

0.296

AC:

25509

AN:

86258

European-Finnish (FIN)

AF:

0.276

AC:

14750

AN:

53410

Middle Eastern (MID)

AF:

0.428

AC:

2470

AN:

5768

European-Non Finnish (NFE)

AF:

0.350

AC:

388664

AN:

1111952

Other (OTH)

AF:

0.352

AC:

21233

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

20603

41206

61810

82413

103016

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12314

24628

36942

49256

61570

<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:

0.363

AC:

55140

AN:

151824

Hom.:

10366

Cov.:

AF XY:

0.359

AC XY:

26667

AN XY:

74194

show subpopulations

African (AFR)

AF:

0.434

AC:

17968

AN:

41354

American (AMR)

AF:

0.365

AC:

5570

AN:

15258

Ashkenazi Jewish (ASJ)

AF:

0.412

AC:

1428

AN:

3470

East Asian (EAS)

AF:

0.185

AC:

949

AN:

5134

South Asian (SAS)

AF:

0.295

AC:

1415

AN:

4800

European-Finnish (FIN)

AF:

0.265

AC:

2794

AN:

10554

Middle Eastern (MID)

AF:

0.422

AC:

124

AN:

294

European-Non Finnish (NFE)

AF:

0.348

AC:

23674

AN:

67940

Other (OTH)

AF:

0.389

AC:

821

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1792

3584

5376

7168

8960

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

514

1028

1542

2056

2570

<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:

0.364

Hom.:

22080

Bravo

AF:

0.374

Asia WGS

AF:

0.286

AC:

993

AN:

3478

EpiCase

AF:

0.366

EpiControl

AF:

0.361

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (10)

not provided (3)

Desmin-related myofibrillar myopathy (2)

Cardiovascular phenotype (1)

Dilated cardiomyopathy 1I (1)

Myofibrillar Myopathy, Dominant (1)

Neurogenic scapuloperoneal syndrome, Kaeser type (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.98

CADD

Benign

0.20

(source)

DANN

Benign

0.90

PhyloP100

-4.3

Mutation Taster

=99/1

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over