rs34365369

Variant names:

• chr2-219418834-G-A
• rs34365369
• NM_001927.4:c.372G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001927.4(DES):​c.372G>A​(p.Glu124Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00357 in 1,583,166 control chromosomes in the GnomAD database, including 169 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (76 hom., cov: 33)
  • Exomes 𝑓: 0.0020 (93 hom.)
• Consequence: DES NM_001927.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:19
• Conservation: PhyloP100: 2.82
• Publications: 3 publications found

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

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 2-219418834-G-A is Benign according to our data. Variant chr2-219418834-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 44258.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-219418834-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 44258.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-219418834-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 44258.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-219418834-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 44258.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-219418834-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 44258.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-219418834-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 44258.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-219418834-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 44258.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-219418834-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 44258.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-219418834-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 44258.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-219418834-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 44258.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-219418834-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 44258.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-219418834-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 44258.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-219418834-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 44258.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-219418834-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 44258.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-219418834-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 44258.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-219418834-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 44258.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-219418834-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 44258.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-219418834-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 44258.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-219418834-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 44258.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-219418834-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 44258.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-219418834-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 44258.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-219418834-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 44258.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-219418834-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 44258.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-219418834-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 44258.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-219418834-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 44258.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-219418834-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 44258.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-219418834-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 44258.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-219418834-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 44258.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-219418834-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 44258.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-219418834-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 44258.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-219418834-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 44258.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-219418834-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 44258.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-219418834-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 44258.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-219418834-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 44258.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-219418834-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 44258.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-219418834-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 44258.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-219418834-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 44258.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-219418834-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 44258.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.82 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0601 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DES	NM_001927.4	c.372G>A	p.Glu124Glu	synonymous_variant	Exon 1 of 9	ENST00000373960.4	NP_001918.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DES	ENST00000373960.4	c.372G>A	p.Glu124Glu	synonymous_variant	Exon 1 of 9	1	NM_001927.4	ENSP00000363071.3

Frequencies

GnomAD3 genomes AF: 0.0179 AC: 2730 AN: 152214 Hom.: 74 Cov.: 33

Gnomad AFR AF: 0.0618

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00687

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.000367

Gnomad OTH AF: 0.0148

GnomAD2 exomes AF: 0.00430 AC: 860 AN: 200182 AF XY: 0.00307

Gnomad AFR exome AF: 0.0564

Gnomad AMR exome AF: 0.00343

Gnomad ASJ exome AF: 0.00142

Gnomad EAS exome AF: 0.000132

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000590

Gnomad OTH exome AF: 0.00366

GnomAD4 exome AF: 0.00203 AC: 2899 AN: 1430836 Hom.: 93 Cov.: 92 AF XY: 0.00184 AC XY: 1307 AN XY: 708732

African (AFR) AF: 0.0667 AC: 2200 AN: 32972

American (AMR) AF: 0.00366 AC: 145 AN: 39664

Ashkenazi Jewish (ASJ) AF: 0.00110 AC: 28 AN: 25542

East Asian (EAS) AF: 0.0000260 AC: 1 AN: 38440

South Asian (SAS) AF: 0.000122 AC: 10 AN: 82024

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50786

Middle Eastern (MID) AF: 0.00995 AC: 57 AN: 5726

European-Non Finnish (NFE) AF: 0.000154 AC: 169 AN: 1096392

Other (OTH) AF: 0.00487 AC: 289 AN: 59290

GnomAD4 genome AF: 0.0180 AC: 2747 AN: 152330 Hom.: 76 Cov.: 33 AF XY: 0.0177 AC XY: 1315 AN XY: 74488

African (AFR) AF: 0.0621 AC: 2581 AN: 41582

American (AMR) AF: 0.00686 AC: 105 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00685 AC: 2 AN: 292

European-Non Finnish (NFE) AF: 0.000367 AC: 25 AN: 68028

Other (OTH) AF: 0.0147 AC: 31 AN: 2116

Alfa AF: 0.00940 Hom.: 15

Bravo AF: 0.0204

Asia WGS AF: 0.00607 AC: 22 AN: 3476

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:19

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:7

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 17, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 26, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:6

Jun 22, 2010

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This silent variant is not expected to have clinical significance because it doe s not alter an amino acid residue and is not located near a splice junction. Fur thermore, it is present in 7% of the African American population (dbSNP;rs343653 69). -

Feb 10, 2016

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 17, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Desmin-related myofibrillar myopathy Benign:2

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Myofibrillar Myopathy, Dominant Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dilated cardiomyopathy 1I Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Neurogenic scapuloperoneal syndrome, Kaeser type Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Oct 28, 2015

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	-0.46
CADD	Benign	15
DANN	Uncertain	0.98
PhyloP100		2.8
PromoterAI		-0.10	Neutral
Mutation Taster		=74/26	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs34365369; hg19: chr2-220283556; COSMIC: COSV104688328; COSMIC: COSV104688328;