rs1553603440

chr2-219420526-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001927.4(DES):c.767A>G(p.Glu256Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000205 in 1,461,762 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. E256E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: DES NM_001927.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.34

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.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DES	NM_001927.4	c.767A>G	p.Glu256Gly	missense_variant	4/9	ENST00000373960.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DES	ENST00000373960.4	c.767A>G	p.Glu256Gly	missense_variant	4/9	1	NM_001927.4	P1
DES	ENST00000477226.6	n.241A>G		non_coding_transcript_exon_variant	3/8	4
DES	ENST00000492726.1	n.162A>G		non_coding_transcript_exon_variant	3/6	4
DES	ENST00000683013.1	n.155A>G		non_coding_transcript_exon_variant	2/7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000205 AC: 30 AN: 1461762 Hom.: 0 Cov.: 35 AF XY: 0.0000179 AC XY: 13 AN XY: 727174

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: 0.0000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Desmin-related myofibrillar myopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Apr 11, 2019

In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C65"). This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a DES-related disease. This sequence change replaces glutamic acid with glycine at codon 256 of the DES protein (p.Glu256Gly). The glutamic acid residue is highly conserved and there is a moderate physicochemical difference between glutamic acid and glycine. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 01, 2023

The p.E256G variant (also known as c.767A>G), located in coding exon 4 of the DES gene, results from an A to G substitution at nucleotide position 767. The glutamic acid at codon 256 is replaced by glycine, an amino acid with similar properties. This amino acid position is well 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
CardioboostCm	Benign	0.0010
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.70	D
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.84	T
M_CAP	Uncertain	0.26	D
MetaRNN	Uncertain	0.48	T
MetaSVM	Uncertain	0.71	D
MutationAssessor	Benign	0.47	N
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-3.2	D
REVEL	Pathogenic	0.82
Sift	Benign	0.10	T
Sift4G	Benign	0.20	T
Polyphen		0.88	P
Vest4		0.39
MutPred		0.53		Loss of disorder (P = 0.0905);
MVP		0.98
MPC		0.73
ClinPred		0.94	D
GERP RS		4.7
Varity_R		0.30
gMVP		0.54

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: rs1553603440; hg19: chr2-220285248;