rs267607486

chr2-219420346-G-Achr2-219420346-G-Cchr2-219420346-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_001927.4(DES):c.735G>A(p.Glu245=) variant causes a splice region, synonymous change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DES NM_001927.4 splice_region, synonymous
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 8.00

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.
• PP5: Variant 2-219420346-G-A is Pathogenic according to our data. Variant chr2-219420346-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 281234.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=2, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DES	NM_001927.4	c.735G>A	p.Glu245=	splice_region_variant, synonymous_variant	3/9	ENST00000373960.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DES	ENST00000373960.4	c.735G>A	p.Glu245=	splice_region_variant, synonymous_variant	3/9	1	NM_001927.4	P1
DES	ENST00000477226.6	n.209G>A		splice_region_variant, non_coding_transcript_exon_variant	2/8	4
DES	ENST00000492726.1	n.130G>A		splice_region_variant, non_coding_transcript_exon_variant	2/6	4
DES	ENST00000683013.1	n.123G>A		splice_region_variant, non_coding_transcript_exon_variant	1/7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 13, 2015	The c.735 G>A variant in the DES gene has not been reported previously as a disease-causing variant nor as a benign polymorphism, to our knowledge. Multiple in silico algorithms indicate that this variant destroys the splice donor site in intron 3. However, in the absence of RNA/functional studies, the actual effect of this sequence change in this individual is unknown. Other splice site variants at the same amino acid position (E245G) and affecting the same donor site (735+1G>A; 735+3A>G) have been reported in the Human Gene Mutation Database in association with desmin-related myopathy (Stenson et al., 2014). The c.735 G>A variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.735 G>A as a variant, likely pathogenic -
Likely pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Nov 19, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 26, 2015	- -

Desmin-related myofibrillar myopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 09, 2020

This sequence change affects codon 245 of the DES mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the DES protein. This variant also falls at the last nucleotide of exon 3 of the DES coding sequence, which is part of the consensus splice site for this exon. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with DES-related conditions. ClinVar contains an entry for this variant (Variation ID: 281234). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.23
Cadd	Uncertain	24
Dann	Benign	0.96

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.30		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.30		Position offset: -12

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

Publications

LitVar

Other links and lift over

dbSNP: rs267607486; hg19: chr2-220285068;