rs144908941

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2PP3_ModerateBS1_Supporting

The NM_001927.4(DES):​c.643G>A​(p.Val215Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000304 in 1,614,082 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

DES
NM_001927.4 missense

Scores

9
8
3

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10B:1

Conservation

PhyloP100: 9.81
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.854
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000145 (22/152202) while in subpopulation AFR AF= 0.000531 (22/41446). AF 95% confidence interval is 0.000359. There are 0 homozygotes in gnomad4. There are 10 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DESNM_001927.4 linkc.643G>A p.Val215Met missense_variant Exon 3 of 9 ENST00000373960.4 NP_001918.3 P17661Q53SB5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
DESENST00000373960.4 linkc.643G>A p.Val215Met missense_variant Exon 3 of 9 1 NM_001927.4 ENSP00000363071.3 P17661
DESENST00000477226.6 linkn.117G>A non_coding_transcript_exon_variant Exon 2 of 8 4
DESENST00000492726.1 linkn.38G>A non_coding_transcript_exon_variant Exon 2 of 6 4
DESENST00000683013.1 linkn.31G>A non_coding_transcript_exon_variant Exon 1 of 7

Frequencies

GnomAD3 genomes
AF:
0.000145
AC:
22
AN:
152202
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000531
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000596
AC:
15
AN:
251468
Hom.:
0
AF XY:
0.0000294
AC XY:
4
AN XY:
135912
show subpopulations
Gnomad AFR exome
AF:
0.000615
Gnomad AMR exome
AF:
0.0000578
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000185
AC:
27
AN:
1461880
Hom.:
0
Cov.:
35
AF XY:
0.0000165
AC XY:
12
AN XY:
727238
show subpopulations
Gnomad4 AFR exome
AF:
0.000478
Gnomad4 AMR exome
AF:
0.0000447
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000450
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.000145
AC:
22
AN:
152202
Hom.:
0
Cov.:
32
AF XY:
0.000134
AC XY:
10
AN XY:
74352
show subpopulations
Gnomad4 AFR
AF:
0.000531
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000823
Hom.:
0
Bravo
AF:
0.000155
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000576
AC:
7

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:10Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:4
Mar 28, 2017
Eurofins Ntd Llc (ga)
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 28, 2020
Athena Diagnostics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 07, 2022
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 222542) -

Aug 23, 2019
Revvity Omics, Revvity
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Desmin-related myofibrillar myopathy Uncertain:1
Jan 22, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 215 of the DES protein (p.Val215Met). This variant is present in population databases (rs144908941, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with DES-related conditions. ClinVar contains an entry for this variant (Variation ID: 222542). 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
Dec 10, 2021
New York Genome Center
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.643G>A (p.Val215Met) variant identified in the DES gene substitutes a well conserved Valine for Methionine at amino acid 215/471 (exon 3/9).This variant is found with low frequency in gnomAD(v3.1.2)(22 heterozygotes, 0 homozygotes; allele frequency:1.45e-4) suggesting it is not a common benign variant in the populations represented in that database. In silico algorithms predict this variant to be Damaging (SIFT; score:0.028) and Pathogenic (REVEL; score:0.782) to the function of the canonical transcript. This variant is reported as a Variant of Uncertain Significance in ClinVar (VarID:222542), and to our current knowledge has not been reported in affected individuals in the literature. The p.Val215 residue is within Coil 1B domain of DES (UniProtKB:P17661). Given the lack of compelling evidence for its pathogenicity, the c.643G>A (p.Val215Met) variant identified in the DES gene is reported as a Variant of Uncertain Significance. -

Desmin-related myofibrillar myopathy;C1858154:Dilated cardiomyopathy 1I;C1867005:Neurogenic scapuloperoneal syndrome, Kaeser type Uncertain:1
Aug 24, 2021
Fulgent Genetics, Fulgent Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Primary familial hypertrophic cardiomyopathy Uncertain:1
Aug 26, 2015
Blueprint Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

DES-related disorder Uncertain:1
Aug 10, 2023
PreventionGenetics, part of Exact Sciences
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The DES c.643G>A variant is predicted to result in the amino acid substitution p.Val215Met. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.044% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-220284976-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Cardiovascular phenotype Uncertain:1
Dec 09, 2022
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.V215M variant (also known as c.643G>A), located in coding exon 3 of the DES gene, results from a G to A substitution at nucleotide position 643. The valine at codon 215 is replaced by methionine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not specified Benign:1
Aug 08, 2023
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.93
CardioboostCm
Benign
0.018
BayesDel_addAF
Uncertain
0.059
T
BayesDel_noAF
Pathogenic
0.20
CADD
Pathogenic
32
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.78
D
Eigen
Pathogenic
0.82
Eigen_PC
Pathogenic
0.76
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.93
D
M_CAP
Uncertain
0.23
D
MetaRNN
Pathogenic
0.85
D
MetaSVM
Pathogenic
0.87
D
MutationAssessor
Uncertain
2.7
M
PrimateAI
Pathogenic
0.85
D
PROVEAN
Uncertain
-2.6
D
REVEL
Pathogenic
0.78
Sift
Uncertain
0.028
D
Sift4G
Benign
0.062
T
Polyphen
1.0
D
Vest4
0.86
MVP
0.97
MPC
0.027
ClinPred
0.42
T
GERP RS
4.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.6
Varity_R
0.33
gMVP
0.78

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.

Other links and lift over

dbSNP: rs144908941; hg19: chr2-220284976; COSMIC: COSV64660495; COSMIC: COSV64660495; API