rs58687088

Positions:

• chr2-219421409-GACA-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PM4_Supporting PP5

The NM_001927.4(DES):​c.1097_1099del​(p.Asn366del) variant causes a 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).

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

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 6 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 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 id is 16832.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1, not_provided=1}. Variant chr2-219421409-GACA-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DES	NM_001927.4	c.1097_1099del	p.Asn366del	inframe_deletion	6/9	ENST00000373960.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DES	ENST00000373960.4	c.1097_1099del	p.Asn366del	inframe_deletion	6/9	1	NM_001927.4	P1
DES	ENST00000477226.6	n.571_573del		non_coding_transcript_exon_variant	5/8	4
DES	ENST00000492726.1	n.492_494del		non_coding_transcript_exon_variant	5/6	4
DES	ENST00000683013.1	n.485_487del		non_coding_transcript_exon_variant	4/7

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

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Desmin-related myofibrillar myopathy Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Apr 24, 2023	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. Experimental studies have shown that this variant affects DES function (PMID: 14648196, 17188893). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. This variant has been observed in individual(s) with desminopathy and/or limb-girdle muscular dystrophy (PMID: 14648196, 32576226). This variant is not present in population databases (gnomAD no frequency). This variant, c.1097_1099del, results in the deletion of 1 amino acid(s) of the DES protein (p.Asn366del), but otherwise preserves the integrity of the reading frame. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2004	- -

not provided Pathogenic:1 Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 28, 2022	This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been identified heterozygous in at least one patient with myopathy or limb-girdle muscular dystrophy (LGMD). Assessment of experimental evidence suggests this variant results in abnormal protein function. Variant proteins are unable to form functional filaments (PMID: 14648196). -
not provided, no classification provided	literature only	Epithelial Biology; Institute of Medical Biology, Singapore	-	- -

Computational scores

Source: dbNSFP v4.3

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: rs58687088; hg19: chr2-220286131;