rs1553603732

Positions:

• chr2-219423783-TCTCCCCATCCAGACCTA-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The ENST00000373960.4(DES):​c.1255_1271del​(p.Pro419CysfsTer10) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: DES ENST00000373960.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 6.67

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 Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-219423783-TCTCCCCATCCAGACCTA-T is Pathogenic according to our data. Variant chr2-219423783-TCTCCCCATCCAGACCTA-T is described in ClinVar as [Pathogenic]. Clinvar id is 522796.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DES	NM_001927.4	c.1255_1271del	p.Pro419CysfsTer10	frameshift_variant	7/9	ENST00000373960.4	NP_001918.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DES	ENST00000373960.4	c.1255_1271del	p.Pro419CysfsTer10	frameshift_variant	7/9	1	NM_001927.4	ENSP00000363071	P1
DES	ENST00000477226.6	n.729_745del		non_coding_transcript_exon_variant	6/8	4
DES	ENST00000492726.1	n.650_666del		non_coding_transcript_exon_variant	6/6	4
DES	ENST00000683013.1	n.643_659del		non_coding_transcript_exon_variant	5/7

Frequencies

GnomAD3 genomes Cov.: 31

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

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Desmin-related myofibrillar myopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Undiagnosed Diseases Network, NIH

Jan 31, 2017

This frameshift mutation is categorized as deleterious according to ACMG guidelines (PMID: 18414213) and was found homozygous in an 18-year-old male with congenital hypotonia, motor delay, progressive muscle weakness, bilateral ptosis, ophthalmoparesis, tachycardia, myopathy on EMG, mild left median neuropathy on NCV, and ragged red fibers. In this consanguineous family, the variant segregated with disease in two affected siblings and 5 affected cousins. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jun 01, 2021

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1553603732; hg19: chr2-220288505;