rs1058284

Positions:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001927.4(DES):c.1104G>A(p.Ala368=) 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:17

Conservation

PhyloP100: -4.32

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 44245.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-219421420-G-A is described in Lovd as [Benign].

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DES	NM_001927.4 linkuse as main transcript	c.1104G>A	p.Ala368=	synonymous_variant	6/9	ENST00000373960.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
DES	ENST00000373960.4 linkuse as main transcript	c.1104G>A	p.Ala368=	synonymous_variant	6/9	1	NM_001927.4	P1
DES	ENST00000477226.6 linkuse as main transcript	n.578G>A		non_coding_transcript_exon_variant	5/8	4
DES	ENST00000492726.1 linkuse as main transcript	n.499G>A		non_coding_transcript_exon_variant	5/6	4
DES	ENST00000683013.1 linkuse as main transcript	n.492G>A		non_coding_transcript_exon_variant	4/7

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

GnomAD3 exomes

AF:

0.332

AC:

83512

AN:

251348

Hom.:

14337

AF XY:

0.333

AC XY:

45208

AN XY:

135870

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 SAS exome

AF:

0.298

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

Gnomad4 AFR exome

AF:

0.440

Gnomad4 AMR exome

AF:

0.316

Gnomad4 ASJ exome

AF:

0.415

Gnomad4 EAS exome

AF:

0.183

Gnomad4 SAS exome

AF:

0.296

Gnomad4 FIN exome

AF:

0.276

Gnomad4 NFE exome

AF:

0.350

Gnomad4 OTH exome

AF:

0.352

GnomAD4 genome

AF:

0.363

AC:

55140

AN:

151824

Hom.:

10366

Cov.:

AF XY:

0.359

AC XY:

26667

AN XY:

74194

show subpopulations

Gnomad4 AFR

AF:

0.434

Gnomad4 AMR

AF:

0.365

Gnomad4 ASJ

AF:

0.412

Gnomad4 EAS

AF:

0.185

Gnomad4 SAS

AF:

0.295

Gnomad4 FIN

AF:

0.265

Gnomad4 NFE

AF:

0.348

Gnomad4 OTH

AF:

0.389

Alfa

AF:

0.363

Hom.:

16682

Bravo

AF:

0.374

Asia WGS

AF:

0.286

AC:

993

AN:

3478

EpiCase

AF:

0.366

EpiControl

AF:

0.361

ClinVar

Significance: Benign

Submissions summary: Benign:17

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:9

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 15, 2008	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 17, 2016	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Desmin-related myofibrillar myopathy

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 12, 2017	- -

Dilated cardiomyopathy 1I

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Myofibrillar Myopathy, Dominant

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Neurogenic scapuloperoneal syndrome, Kaeser type

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 27, 2015

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.98

CADD

Benign

0.20

DANN

Benign

0.90

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over