Genetic Variant DES:p.Pro25Pro (chr2-219418537-A-G) – 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.75A>G(p.Pro25Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.972 in 1,602,894 control chromosomes in the GnomAD database, including 760,892 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P25P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.90 ( 62755 hom., cov: 34)

Exomes 𝑓: 0.98 ( 698137 hom. )

Consequence

DES
NM_001927.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:22

Conservation

PhyloP100: 0.0430

Publications

16 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BP6

Variant 2-219418537-A-G is Benign according to our data. Variant chr2-219418537-A-G is described in ClinVar as Benign. ClinVar VariationId is 36002.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.043 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.982 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.75A>G	p.Pro25Pro	synonymous	Exon 1 of 9	NP_001918.3
DES	NM_001382708.1		c.75A>G	p.Pro25Pro	synonymous	Exon 1 of 9	NP_001369637.1
DES	NM_001382712.1		c.75A>G	p.Pro25Pro	synonymous	Exon 1 of 9	NP_001369641.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DES	ENST00000373960.4	TSL:1 MANE Select	c.75A>G	p.Pro25Pro	synonymous	Exon 1 of 9	ENSP00000363071.3
DES	ENST00000942906.1		c.75A>G	p.Pro25Pro	synonymous	Exon 1 of 10	ENSP00000612965.1
DES	ENST00000942898.1		c.75A>G	p.Pro25Pro	synonymous	Exon 1 of 9	ENSP00000612957.1

Frequencies

GnomAD3 genomes

AF:

0.897

AC:

136433

AN:

152046

Hom.:

62740

Cov.:

show subpopulations

Gnomad AFR

AF:

0.667

Gnomad AMI

AF:

0.999

Gnomad AMR

AF:

0.956

Gnomad ASJ

AF:

0.986

Gnomad EAS

AF:

1.00

Gnomad SAS

AF:

0.976

Gnomad FIN

AF:

0.997

Gnomad MID

AF:

0.962

Gnomad NFE

AF:

0.988

Gnomad OTH

AF:

0.918

GnomAD2 exomes

AF:

0.968

AC:

217879

AN:

225084

AF XY:

0.972

show subpopulations

Gnomad AFR exome

AF:

0.643

Gnomad AMR exome

AF:

0.979

Gnomad ASJ exome

AF:

0.989

Gnomad EAS exome

AF:

1.00

Gnomad FIN exome

AF:

0.998

Gnomad NFE exome

AF:

0.989

Gnomad OTH exome

AF:

0.978

GnomAD4 exome

AF:

0.980

AC:

1421249

AN:

1450738

Hom.:

698137

Cov.:

AF XY:

0.981

AC XY:

707505

AN XY:

721554

show subpopulations

African (AFR)

AF:

0.651

AC:

21145

AN:

32498

American (AMR)

AF:

0.977

AC:

42676

AN:

43692

Ashkenazi Jewish (ASJ)

AF:

0.988

AC:

25354

AN:

25668

East Asian (EAS)

AF:

1.00

AC:

38769

AN:

38774

South Asian (SAS)

AF:

0.974

AC:

82807

AN:

85058

European-Finnish (FIN)

AF:

0.997

AC:

51126

AN:

51276

Middle Eastern (MID)

AF:

0.964

AC:

5465

AN:

5668

European-Non Finnish (NFE)

AF:

0.989

AC:

1096139

AN:

1108318

Other (OTH)

AF:

0.966

AC:

57768

AN:

59786

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

1489

2977

4466

5954

7443

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21598

43196

64794

86392

107990

<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:

0.897

AC:

136489

AN:

152156

Hom.:

62755

Cov.:

AF XY:

0.901

AC XY:

66986

AN XY:

74386

show subpopulations

African (AFR)

AF:

0.667

AC:

27634

AN:

41456

American (AMR)

AF:

0.956

AC:

14631

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.986

AC:

3421

AN:

3470

East Asian (EAS)

AF:

1.00

AC:

5133

AN:

5134

South Asian (SAS)

AF:

0.976

AC:

4718

AN:

4832

European-Finnish (FIN)

AF:

0.997

AC:

10594

AN:

10624

Middle Eastern (MID)

AF:

0.959

AC:

280

AN:

292

European-Non Finnish (NFE)

AF:

0.988

AC:

67225

AN:

68016

Other (OTH)

AF:

0.919

AC:

1942

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

579

1158

1736

2315

2894

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

886

1772

2658

3544

4430

<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:

0.973

Hom.:

17041

Bravo

AF:

0.885

Asia WGS

AF:

0.965

AC:

3348

AN:

3470

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (10)

Desmin-related myofibrillar myopathy (3)

Dilated cardiomyopathy 1I (2)

Neurogenic scapuloperoneal syndrome, Kaeser type (2)

not provided (2)

Cardiomyopathy (1)

Cardiovascular phenotype (1)

Myofibrillar Myopathy, Dominant (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

(source)

DANN

Benign

0.64

PhyloP100

0.043

PromoterAI

-0.015

Neutral

(source)

Mutation Taster

=98/2

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