rs58687088

Variant names:

• chr2-219421409-GACA-G
• rs58687088
• NM_001927.4:c.1097_1099delACA

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PS3 PM1 PM2 PM4_Supporting PP5

The NM_001927.4(DES):​c.1097_1099delACA​(p.Asn366del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV002770672: Assessment of experimental evidence suggests this variant results in abnormal protein function. Variant proteins are unable to form functional filaments (PMID:14648196).".

• Frequency: Genomes: not found (cov: 32)
• Consequence: DES NM_001927.4 disruptive_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1 O:1
• Conservation: PhyloP100: 7.25
• Publications: 8 publications found

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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• myofibrillar myopathy

  Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen
• myofibrillar myopathy 1

  Inheritance: SD, AD, AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• atrioventricular block

  Inheritance: AR, AD 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

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV002770672: Assessment of experimental evidence suggests this variant results in abnormal protein function. Variant proteins are unable to form functional filaments (PMID: 14648196).
• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 22 uncertain in NM_001927.4
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_001927.4. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 2-219421409-GACA-G is Pathogenic according to our data. Variant chr2-219421409-GACA-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 16832.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001927.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DES	NM_001927.4	MANE Select	c.1097_1099delACA	p.Asn366del	disruptive_inframe_deletion	Exon 6 of 9	NP_001918.3
	DES	NM_001382708.1		c.1094_1096delACA	p.Asn365del	disruptive_inframe_deletion	Exon 6 of 9	NP_001369637.1
	DES	NM_001382712.1		c.1097_1099delACA	p.Asn366del	disruptive_inframe_deletion	Exon 6 of 9	NP_001369641.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DES	ENST00000373960.4	TSL:1 MANE Select	c.1097_1099delACA	p.Asn366del	disruptive_inframe_deletion	Exon 6 of 9	ENSP00000363071.3	P17661
	DES	ENST00000942906.1		c.1097_1099delACA	p.Asn366del	disruptive_inframe_deletion	Exon 6 of 10	ENSP00000612965.1
	DES	ENST00000942898.1		c.1097_1099delACA	p.Asn366del	disruptive_inframe_deletion	Exon 6 of 9	ENSP00000612957.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	1	-	Desmin-related myofibrillar myopathy (2)
1	-	-	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.3
Mutation Taster		=53/47	polymorphism

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

Other links and lift over

dbSNP: rs58687088; hg19: chr2-220286131;