2-219418632-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 1P and 7B. PP2BP4_ModerateBP6BS1

The NM_001927.4(DES):c.170C>T(p.Ser57Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000178 in 1,599,882 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S57S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00070 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00012 ( 1 hom. )

Consequence

DES
NM_001927.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:12B:5

Conservation

PhyloP100: 3.70

Publications

4 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: 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

DES links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

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=0.19815353).

BP6

Variant 2-219418632-C-T is Benign according to our data. Variant chr2-219418632-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 44254.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000697 (106/152170) while in subpopulation AMR AF = 0.00288 (44/15300). AF 95% confidence interval is 0.0022. There are 0 homozygotes in GnomAd4. There are 62 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DES	NM_001927.4 link	c.170C>T	p.Ser57Leu	missense_variant	Exon 1 of 9	ENST00000373960.4	NP_001918.3	P17661Q53SB5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DES	ENST00000373960.4 link	c.170C>T	p.Ser57Leu	missense_variant	Exon 1 of 9	1	NM_001927.4	ENSP00000363071.3		P17661

Frequencies

GnomAD3 genomes

AF:

0.000697

AC:

106

AN:

152058

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00138

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00288

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000289

AC:

AN:

218216

AF XY:

0.000250

show subpopulations

Gnomad AFR exome

AF:

0.00105

Gnomad AMR exome

AF:

0.000749

Gnomad ASJ exome

AF:

0.000447

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000188

Gnomad OTH exome

AF:

0.000752

GnomAD4 exome

AF:

0.000123

AC:

178

AN:

1447712

Hom.:

Cov.:

AF XY:

0.000117

AC XY:

AN XY:

718684

show subpopulations

African (AFR)

AF:

0.00117

AC:

AN:

33218

American (AMR)

AF:

0.000788

AC:

AN:

43134

Ashkenazi Jewish (ASJ)

AF:

0.000353

AC:

AN:

25482

East Asian (EAS)

AF:

0.00

AC:

AN:

39326

South Asian (SAS)

AF:

0.00

AC:

AN:

84300

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51086

Middle Eastern (MID)

AF:

0.000874

AC:

AN:

5718

European-Non Finnish (NFE)

AF:

0.0000479

AC:

AN:

1105732

Other (OTH)

AF:

0.000636

AC:

AN:

59716

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.000697

AC:

106

AN:

152170

Hom.:

Cov.:

AF XY:

0.000833

AC XY:

AN XY:

74400

show subpopulations

African (AFR)

AF:

0.00137

AC:

AN:

41534

American (AMR)

AF:

0.00288

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5144

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

67970

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.520

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000330

Hom.:

Bravo

AF:

0.000941

ESP6500AA

AF:

0.000965

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000186

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:12Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:7Benign:1

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

DES: PP3, BS2 -

Jun 12, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Functional studies showed p.(S57L) results in similar desmin aggregates but different location of the protein compared to wild type (PMID: 32235386); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30564623, 20718792, 26272908, 32235386, 34935411, 30847666) -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 25, 2018

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 14, 2023

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 30, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PP4, PS4_moderate -

not specified

Uncertain:2Benign:2

Sep 30, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant classified as Uncertain Significance - Favor Benign. The Ser57Leu varian t in DES has been previously identified by our laboratory in 1 toddler with LVNC and 1 teenager with reduced LV function. This variant has also been identified in 0.1% (4/4142) of African American chromosomes by the NHLBI Exome Sequencing P roject (http://evs.gs.washington.edu/EVS/; dbSNP rs372825868). Computational pre diction tools and conservation analysis suggest this variant may impact the prot ein, though this information is not predictive enough to determine pathogenicity . In summary, while the clinical significance of the Ser57Leu variant is uncerta in, its frequency suggests that it is more likely to be benign. -

Feb 16, 2017

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BS1 -

Feb 10, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: DES c.170C>T (p.Ser57Leu) results in a non-conservative amino acid change located in the Intermediate filament head, DNA-binding domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00029 in 218216 control chromosomes. The observed variant frequency is approximately 11.55 fold of the estimated maximal expected allele frequency for a pathogenic variant in DES causing Cardiomyopathy phenotype (2.5e-05). c.170C>T has been reported in the literature in individuals affected with Cardiomyopathy (e.g., Santori_2015, Kubnek_2020, Khan_2022). However, these report(s) do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 34935411, 32235386, 26272908). ClinVar contains an entry for this variant (Variation ID: 44254). Based on the evidence outlined above, the variant was classified as likely benign. -

Desmin-related myofibrillar myopathy

Uncertain:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 57 of the DES protein (p.Ser57Leu). This variant is present in population databases (rs372825868, gnomAD 0.1%). This missense change has been observed in individual(s) with sudden unexpected death, dilated cardiomyopathy and hypertrophic cardiomyopathy (PMID: 26272908, 30847666, 32235386). ClinVar contains an entry for this variant (Variation ID: 44254). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on DES protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Dilated cardiomyopathy 1I

Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Neurogenic scapuloperoneal syndrome, Kaeser type

Benign:1

Jan 12, 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

Dec 02, 2022

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely 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

AlphaMissense

Benign

0.31

CardioboostCm

Benign

0.0079

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Uncertain

-0.040

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.53

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.89

M_CAP

Pathogenic

0.36

MetaRNN

Benign

0.20

MetaSVM

Uncertain

-0.077

MutationAssessor

Benign

1.0

PhyloP100

3.7

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-1.9

REVEL

Uncertain

0.57

Sift

Benign

0.076

Sift4G

Uncertain

0.055

Polyphen

0.90

Vest4

0.65

MVP

0.92

MPC

0.80

ClinPred

0.017

GERP RS

5.1

PromoterAI

0.016

Neutral

(source)

Varity_R

0.43

gMVP

0.76

Mutation Taster

=63/37

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over