rs12920

Positions:

• chr2-219420944-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001927.4(DES):​c.1014G>C​(p.Leu338Leu) 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 1,612,460 control chromosomes in the GnomAD database, including 97,380 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.37 (10515 hom., cov: 32)
  • Exomes 𝑓: 0.34 (86865 hom.)
• Consequence: DES NM_001927.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: 0.307

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 2-219420944-G-C is Benign according to our data. Variant chr2-219420944-G-C is described in ClinVar as [Benign]. Clinvar id is 44242.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-219420944-G-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.307 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.437 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DES	NM_001927.4	c.1014G>C	p.Leu338Leu	synonymous_variant	5/9	ENST00000373960.4	NP_001918.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DES	ENST00000373960.4	c.1014G>C	p.Leu338Leu	synonymous_variant	5/9	1	NM_001927.4	ENSP00000363071.3
DES	ENST00000477226.6	n.488G>C		non_coding_transcript_exon_variant	4/8	4
DES	ENST00000492726.1	n.409G>C		non_coding_transcript_exon_variant	4/6	4
DES	ENST00000683013.1	n.402G>C		non_coding_transcript_exon_variant	3/7

Frequencies

GnomAD3 genomes AF: 0.365 AC: 55466 AN: 151860 Hom.: 10495 Cov.: 32

Gnomad AFR AF: 0.443

Gnomad AMI AF: 0.436

Gnomad AMR AF: 0.366

Gnomad ASJ AF: 0.412

Gnomad EAS AF: 0.183

Gnomad SAS AF: 0.297

Gnomad FIN AF: 0.265

Gnomad MID AF: 0.418

Gnomad NFE AF: 0.348

Gnomad OTH AF: 0.383

GnomAD3 exomes AF: 0.332 AC: 82565 AN: 248902 Hom.: 14025 AF XY: 0.332 AC XY: 44649 AN XY: 134518

Gnomad AFR exome AF: 0.447

Gnomad AMR exome AF: 0.310

Gnomad ASJ exome AF: 0.421

Gnomad EAS exome AF: 0.189

Gnomad SAS exome AF: 0.297

Gnomad FIN exome AF: 0.278

Gnomad NFE exome AF: 0.355

Gnomad OTH exome AF: 0.358

GnomAD4 exome AF: 0.342 AC: 499361 AN: 1460484 Hom.: 86865 Cov.: 49 AF XY: 0.341 AC XY: 247620 AN XY: 726460

Gnomad4 AFR exome AF: 0.449

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: 0.352

GnomAD4 genome AF: 0.365 AC: 55522 AN: 151976 Hom.: 10515 Cov.: 32 AF XY: 0.362 AC XY: 26870 AN XY: 74302

Gnomad4 AFR AF: 0.443

Gnomad4 AMR AF: 0.365

Gnomad4 ASJ AF: 0.412

Gnomad4 EAS AF: 0.183

Gnomad4 SAS AF: 0.296

Gnomad4 FIN AF: 0.265

Gnomad4 NFE AF: 0.348

Gnomad4 OTH AF: 0.390

Alfa AF: 0.363 Hom.: 3228

Bravo AF: 0.377

Asia WGS AF: 0.286 AC: 996 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:18

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:9

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 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	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 12, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 12, 2017	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Desmin-related myofibrillar myopathy Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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

- -

Dilated cardiomyopathy 1I Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

Neurogenic scapuloperoneal syndrome, Kaeser type Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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	-0.55
CADD	Benign	11
DANN	Benign	0.75

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: rs12920; hg19: chr2-220285666; COSMIC: COSV64659785; COSMIC: COSV64659785;