Genetic Variant NM_001927.4:c.1014G>C (chr2-219420944-G-C) – 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.1014G>C(p.Leu338Leu) 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 1,612,460 control chromosomes in the GnomAD database, including 97,380 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.37 ( 10515 hom., cov: 32)

Exomes 𝑓: 0.34 ( 86865 hom. )

Consequence

DES
NM_001927.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.307

Publications

17 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=-0.55).

BP6

Variant 2-219420944-G-C is Benign according to our data. Variant chr2-219420944-G-C is described in ClinVar as Benign. ClinVar VariationId is 44242.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.307 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.437 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.1014G>C	p.Leu338Leu	synonymous	Exon 5 of 9	NP_001918.3
DES	NM_001382708.1		c.1011G>C	p.Leu337Leu	synonymous	Exon 5 of 9	NP_001369637.1
DES	NM_001382712.1		c.1014G>C	p.Leu338Leu	synonymous	Exon 5 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.1014G>C	p.Leu338Leu	synonymous	Exon 5 of 9	ENSP00000363071.3	P17661
DES	ENST00000942906.1		c.1014G>C	p.Leu338Leu	synonymous	Exon 5 of 10	ENSP00000612965.1
DES	ENST00000942898.1		c.1014G>C	p.Leu338Leu	synonymous	Exon 5 of 9	ENSP00000612957.1

Frequencies

GnomAD3 genomes

AF:

0.365

AC:

55466

AN:

151860

Hom.:

10495

Cov.:

show subpopulations

Gnomad AFR

AF:

0.443

Gnomad AMI

AF:

0.436

Gnomad AMR

AF:

0.366

Gnomad ASJ

AF:

0.412

Gnomad EAS

AF:

0.183

Gnomad SAS

AF:

0.297

Gnomad FIN

AF:

0.265

Gnomad MID

AF:

0.418

Gnomad NFE

AF:

0.348

Gnomad OTH

AF:

0.383

GnomAD2 exomes

AF:

0.332

AC:

82565

AN:

248902

AF XY:

0.332

show subpopulations

Gnomad AFR exome

AF:

0.447

Gnomad AMR exome

AF:

0.310

Gnomad ASJ exome

AF:

0.421

Gnomad EAS exome

AF:

0.189

Gnomad FIN exome

AF:

0.278

Gnomad NFE exome

AF:

0.355

Gnomad OTH exome

AF:

0.358

GnomAD4 exome

AF:

0.342

AC:

499361

AN:

1460484

Hom.:

86865

Cov.:

AF XY:

0.341

AC XY:

247620

AN XY:

726460

show subpopulations

African (AFR)

AF:

0.449

AC:

15026

AN:

33444

American (AMR)

AF:

0.316

AC:

14089

AN:

44572

Ashkenazi Jewish (ASJ)

AF:

0.415

AC:

10851

AN:

26122

East Asian (EAS)

AF:

0.183

AC:

7264

AN:

39654

South Asian (SAS)

AF:

0.296

AC:

25462

AN:

86162

European-Finnish (FIN)

AF:

0.276

AC:

14603

AN:

52994

Middle Eastern (MID)

AF:

0.428

AC:

2468

AN:

5762

European-Non Finnish (NFE)

AF:

0.349

AC:

388354

AN:

1111424

Other (OTH)

AF:

0.352

AC:

21244

AN:

60350

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

20800

41601

62401

83202

104002

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12312

24624

36936

49248

61560

<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:

0.365

AC:

55522

AN:

151976

Hom.:

10515

Cov.:

AF XY:

0.362

AC XY:

26870

AN XY:

74302

show subpopulations

African (AFR)

AF:

0.443

AC:

18332

AN:

41422

American (AMR)

AF:

0.365

AC:

5582

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.412

AC:

1431

AN:

3472

East Asian (EAS)

AF:

0.183

AC:

943

AN:

5154

South Asian (SAS)

AF:

0.296

AC:

1427

AN:

4822

European-Finnish (FIN)

AF:

0.265

AC:

2799

AN:

10568

Middle Eastern (MID)

AF:

0.422

AC:

124

AN:

294

European-Non Finnish (NFE)

AF:

0.348

AC:

23664

AN:

67942

Other (OTH)

AF:

0.390

AC:

823

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1795

3590

5384

7179

8974

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:

0.363

Hom.:

3228

Bravo

AF:

0.377

Asia WGS

AF:

0.286

AC:

996

AN:

3478

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

-0.55

CADD

Benign

(source)

DANN

Benign

0.75

PhyloP100

0.31

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over