rs727504877

chr2-219418541-G-Achr2-219418541-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_001927.4(DES):c.79G>A(p.Gly27Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000749 in 1,601,728 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G27D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0000069 (0 hom.)
• Consequence: DES NM_001927.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:9
• Conservation: PhyloP100: 6.49

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 Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a region_of_interest Head (size 106) in uniprot entity DESM_HUMAN there are 24 pathogenic changes around while only 2 benign (92%) in NM_001927.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20816237).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DES	NM_001927.4	c.79G>A	p.Gly27Ser	missense_variant	1/9	ENST00000373960.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DES	ENST00000373960.4	c.79G>A	p.Gly27Ser	missense_variant	1/9	1	NM_001927.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152112 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000690 AC: 10 AN: 1449616 Hom.: 0 Cov.: 72 AF XY: 0.00000971 AC XY: 7 AN XY: 720998

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000903

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152112 Hom.: 0 Cov.: 34 AF XY: 0.0000135 AC XY: 1 AN XY: 74306

Gnomad4 AFR AF: 0.00

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: 0.0000294

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:6

Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 10, 2016	A variant of uncertain significance has been identified in the DES gene. While the G27S variant has not been published as a pathogenic or a benign variant to our knowledge, it has been classified as a variant of uncertain significance by another clinical laboratory in ClinVar (SCV000205960.3; Landrum et al., 2016). The G27S variant was not observed in approximately 5,600 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project (average read depth 8.0). The G27S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position that is conserved only in mammals. Finally, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign. -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Desmin-related myofibrillar myopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

May 27, 2022

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 27 of the DES protein (p.Gly27Ser). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with myopathy (PMID: 22215463). ClinVar contains an entry for this variant (Variation ID: 179455). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 11, 2013

The Gly27Ser variant in DES has not been previously reported in individuals with cardiomyopathy. Data from large population studies is insufficient to assess th e frequency of this variant. Computational analyses (biochemical amino acid prop erties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide strong supp ort for or against an impact to the protein. Additional information is needed t o fully assess the clinical significance of the Glu838Gln variant. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 27, 2023

The p.G27S variant (also known as c.79G>A), located in coding exon 1 of the DES gene, results from a G to A substitution at nucleotide position 79. The glycine at codon 27 is replaced by serine, an amino acid with similar properties. This variant was detected in a cardiomyopathy genetic testing cohort; however, clinical details were limited, and additional cardiac variants were detected in some cases. (van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
CardioboostCm	Benign	0.022
BayesDel_addAF	Uncertain	0.030	T
BayesDel_noAF	Benign	-0.19
Cadd	Benign	22
Dann	Uncertain	0.98
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.0059
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.69	T
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	-0.43	N
MutationTaster	Benign	0.97	D
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.030	N
REVEL	Uncertain	0.32
Sift	Benign	0.46	T
Sift4G	Benign	0.45	T
Polyphen		0.45	B
Vest4		0.28
MutPred		0.32		Gain of phosphorylation at G27 (P = 0.0244);
MVP		0.89
MPC		0.90
ClinPred		0.55	D
GERP RS		5.1
Varity_R		0.082
gMVP		0.39

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: rs727504877; hg19: chr2-220283263;