Genetic Variant NM_001927.4:c.1375G>A (chr2-219425952-G-A) – ACMG Classification: Benign (-17 pts)

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_001927.4(DES):c.1375G>A(p.Val459Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00171 in 1,613,954 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V459F) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0091 ( 22 hom., cov: 32)

Exomes 𝑓: 0.00095 ( 16 hom. )

Consequence

DES
NM_001927.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:23O:1

Conservation

PhyloP100: 7.24

Publications

14 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:

ENSG00000234638 (HGNC:):

ENSG00000234638 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -17 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_001927.4

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=0.007689148).

BP6

Variant 2-219425952-G-A is Benign according to our data. Variant chr2-219425952-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 44252.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00907 (1380/152156) while in subpopulation AFR AF = 0.0311 (1290/41496). AF 95% confidence interval is 0.0297. There are 22 homozygotes in GnomAd4. There are 655 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 22 AD,AR,SD gene

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.1375G>A	p.Val459Ile	missense	Exon 9 of 9	NP_001918.3
DES	NM_001382708.1		c.1372G>A	p.Val458Ile	missense	Exon 9 of 9	NP_001369637.1
DES	NM_001382711.1		c.1354G>A	p.Val452Ile	missense	Exon 9 of 9	NP_001369640.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DES	ENST00000373960.4	TSL:1 MANE Select	c.1375G>A	p.Val459Ile	missense	Exon 9 of 9	ENSP00000363071.3	P17661
DES	ENST00000942906.1		c.1498G>A	p.Val500Ile	missense	Exon 10 of 10	ENSP00000612965.1
DES	ENST00000942898.1		c.1489G>A	p.Val497Ile	missense	Exon 9 of 9	ENSP00000612957.1

Frequencies

GnomAD3 genomes

AF:

0.00907

AC:

1379

AN:

152038

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0312

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00360

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000265

Gnomad OTH

AF:

0.00718

GnomAD2 exomes

AF:

0.00249

AC:

624

AN:

250812

AF XY:

0.00184

show subpopulations

Gnomad AFR exome

AF:

0.0324

Gnomad AMR exome

AF:

0.00147

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0000463

Gnomad NFE exome

AF:

0.000150

Gnomad OTH exome

AF:

0.000652

GnomAD4 exome

AF:

0.000945

AC:

1382

AN:

1461798

Hom.:

Cov.:

AF XY:

0.000814

AC XY:

592

AN XY:

727198

show subpopulations

African (AFR)

AF:

0.0305

AC:

1022

AN:

33480

American (AMR)

AF:

0.00154

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000638

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000750

AC:

AN:

53344

Middle Eastern (MID)

AF:

0.00156

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000110

AC:

122

AN:

1111992

Other (OTH)

AF:

0.00167

AC:

101

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

180

270

360

450

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

108

144

180

<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:

0.00907

AC:

1380

AN:

152156

Hom.:

Cov.:

AF XY:

0.00881

AC XY:

655

AN XY:

74374

show subpopulations

African (AFR)

AF:

0.0311

AC:

1290

AN:

41496

American (AMR)

AF:

0.00360

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.000208

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000265

AC:

AN:

67982

Other (OTH)

AF:

0.00710

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

131

197

262

328

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00329

Hom.:

Bravo

AF:

0.0100

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0356

AC:

157

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00303

AC:

368

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000356

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (11)

not provided (5)

Desmin-related myofibrillar myopathy (2)

Cardiomyopathy (1)

Cardiovascular phenotype (1)

Dilated cardiomyopathy 1I (1)

Myofibrillar Myopathy, Dominant (1)

Neurogenic scapuloperoneal syndrome, Kaeser type (1)

Primary dilated cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.10

CADD

Benign

(source)

DANN

Benign

0.84

DEOGEN2

Benign

0.071

Eigen

Benign

0.091

Eigen_PC

Benign

0.22

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

MetaRNN

Benign

0.0077

MetaSVM

Uncertain

0.16

MutationAssessor

Benign

0.75

PhyloP100

7.2

PrimateAI

Uncertain

0.62

PROVEAN

Benign

0.0

REVEL

Uncertain

0.43

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.56

Vest4

0.36

MVP

0.90

MPC

0.43

ClinPred

0.028

GERP RS

4.2

Varity_R

0.048

gMVP

0.50

Mutation Taster

=80/20

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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