rs1058261

Positions:

• chr2-219420587-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_001927.4(DES):​c.828C>T​(p.Asp276=) variant causes a synonymous change. The variant allele was found at a frequency of 0.344 in 1,613,578 control chromosomes in the GnomAD database, including 97,279 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.36 (10400 hom., cov: 31)
  • Exomes 𝑓: 0.34 (86879 hom.)
• Consequence: DES NM_001927.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: 4.17

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]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.26).
• BP6: Variant 2-219420587-C-T is Benign according to our data. Variant chr2-219420587-C-T is described in ClinVar as [Benign]. Clinvar id is 44272.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-219420587-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.431 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DES	NM_001927.4	c.828C>T	p.Asp276=	synonymous_variant	4/9	ENST00000373960.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DES	ENST00000373960.4	c.828C>T	p.Asp276=	synonymous_variant	4/9	1	NM_001927.4	P1
DES	ENST00000477226.6	n.302C>T		non_coding_transcript_exon_variant	3/8	4
DES	ENST00000492726.1	n.223C>T		non_coding_transcript_exon_variant	3/6	4
DES	ENST00000683013.1	n.216C>T		non_coding_transcript_exon_variant	2/7

Frequencies

GnomAD3 genomes AF: 0.363 AC: 55129 AN: 151730 Hom.: 10380 Cov.: 31

Gnomad AFR AF: 0.436

Gnomad AMI AF: 0.438

Gnomad AMR AF: 0.363

Gnomad ASJ AF: 0.411

Gnomad EAS AF: 0.184

Gnomad SAS AF: 0.297

Gnomad FIN AF: 0.265

Gnomad MID AF: 0.418

Gnomad NFE AF: 0.348

Gnomad OTH AF: 0.380

GnomAD3 exomes AF: 0.332 AC: 83064 AN: 250232 Hom.: 14247 AF XY: 0.332 AC XY: 44982 AN XY: 135330

Gnomad AFR exome AF: 0.441

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: 0.356

Gnomad OTH exome AF: 0.358

GnomAD4 exome AF: 0.342 AC: 499604 AN: 1461730 Hom.: 86879 Cov.: 55 AF XY: 0.341 AC XY: 247827 AN XY: 727172

Gnomad4 AFR exome AF: 0.443

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: 0.349

Gnomad4 OTH exome AF: 0.351

GnomAD4 genome AF: 0.363 AC: 55183 AN: 151848 Hom.: 10400 Cov.: 31 AF XY: 0.360 AC XY: 26709 AN XY: 74200

Gnomad4 AFR AF: 0.436

Gnomad4 AMR AF: 0.363

Gnomad4 ASJ AF: 0.411

Gnomad4 EAS AF: 0.184

Gnomad4 SAS AF: 0.296

Gnomad4 FIN AF: 0.265

Gnomad4 NFE AF: 0.348

Gnomad4 OTH AF: 0.387

Alfa AF: 0.361 Hom.: 23493

Bravo AF: 0.375

Asia WGS AF: 0.286 AC: 996 AN: 3478

EpiCase AF: 0.366

EpiControl AF: 0.361

ClinVar

Significance: Benign

Submissions summary: Benign:18

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:10

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)	Mar 12, 2013	- -
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	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
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	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 12, 2017	- -
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	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

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. -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 18, 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	-0.26
CADD	Benign	14
DANN	Benign	0.89

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

Other links and lift over

dbSNP: rs1058261; hg19: chr2-220285309; COSMIC: COSV64659827; COSMIC: COSV64659827;