rs200545412

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 1P and 2B. PP2BP4_Moderate

The NM_001927.4(DES):c.250G>A(p.Gly84Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000997 in 1,564,974 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G84G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00010 ( 1 hom. )

Consequence

DES
NM_001927.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10B:1

Conservation

PhyloP100: 3.40

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: Likely_benign. The variant received -1 ACMG points.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 32 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: 1.7729 (below the threshold of 3.09). Trascript score misZ: 0.36303 (below the threshold of 3.09). GenCC associations: The gene is linked to myofibrillar myopathy 1, dilated cardiomyopathy 1I, atrioventricular block, arrhythmogenic right ventricular cardiomyopathy, dilated cardiomyopathy, familial isolated dilated cardiomyopathy, neurogenic scapuloperoneal syndrome, Kaeser type.

BP4

Computational evidence support a benign effect (MetaRNN=0.2356554).

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.250G>A	p.Gly84Ser	missense	Exon 1 of 9	NP_001918.3
DES	NM_001382708.1		c.250G>A	p.Gly84Ser	missense	Exon 1 of 9	NP_001369637.1
DES	NM_001382712.1		c.250G>A	p.Gly84Ser	missense	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.250G>A	p.Gly84Ser	missense	Exon 1 of 9	ENSP00000363071.3
DES	ENST00000942906.1		c.250G>A	p.Gly84Ser	missense	Exon 1 of 10	ENSP00000612965.1
DES	ENST00000942898.1		c.250G>A	p.Gly84Ser	missense	Exon 1 of 9	ENSP00000612957.1

Frequencies

GnomAD3 genomes

AF:

0.0000854

AC:

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000993

AC:

AN:

171168

AF XY:

0.0000876

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000618

Gnomad NFE exome

AF:

0.000217

Gnomad OTH exome

AF:

0.000216

GnomAD4 exome

AF:

0.000101

AC:

143

AN:

1412812

Hom.:

Cov.:

AF XY:

0.000112

AC XY:

AN XY:

698170

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32668

American (AMR)

AF:

0.00

AC:

AN:

36832

Ashkenazi Jewish (ASJ)

AF:

0.0000396

AC:

AN:

25254

East Asian (EAS)

AF:

0.0000268

AC:

AN:

37322

South Asian (SAS)

AF:

0.00

AC:

AN:

80622

European-Finnish (FIN)

AF:

0.000203

AC:

AN:

49296

Middle Eastern (MID)

AF:

0.000176

AC:

AN:

5694

European-Non Finnish (NFE)

AF:

0.000116

AC:

126

AN:

1086598

Other (OTH)

AF:

0.0000683

AC:

AN:

58526

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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:

0.0000854

AC:

AN:

152162

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74336

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41438

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.000191

AC:

AN:

68022

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.567

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000231

Hom.:

Bravo

AF:

0.0000718

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000356

AC:

ExAC

AF:

0.0000871

AC:

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (7)

not specified (2)

Cardiovascular phenotype (1)

Desmin-related myofibrillar myopathy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

CardioboostCm

Benign

0.0043

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.21

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.23

Eigen

Benign

-0.12

Eigen_PC

Benign

-0.080

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.69

M_CAP

Benign

0.064

MetaRNN

Benign

0.24

MetaSVM

Benign

-0.65

MutationAssessor

Benign

1.8

PhyloP100

3.4

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

0.010

REVEL

Benign

0.28

Sift

Benign

0.88

Sift4G

Benign

0.49

Polyphen

0.95

Vest4

0.23

MVP

0.86

MPC

1.3

ClinPred

0.25

GERP RS

2.7

PromoterAI

-0.022

Neutral

(source)

Varity_R

0.038

gMVP

0.78

Mutation Taster

=66/34

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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