rs1553603732

Variant names:

• chr2-219423783-TCTCCCCATCCAGACCTA-T
• rs1553603732
• NM_001927.4:c.1255_1271delCCCATCCAGACCTACTC

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_001927.4(DES):​c.1255_1271delCCCATCCAGACCTACTC​(p.Pro419CysfsTer10) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. P419P) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: DES NM_001927.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 6.67
• Publications: 0 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: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• myofibrillar myopathy 1

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

  Inheritance: AD, AR 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 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 2-219423783-TCTCCCCATCCAGACCTA-T is Pathogenic according to our data. Variant chr2-219423783-TCTCCCCATCCAGACCTA-T is described in ClinVar as Pathogenic. ClinVar VariationId is 522796.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DES	NM_001927.4	c.1255_1271delCCCATCCAGACCTACTC	p.Pro419CysfsTer10	frameshift_variant	Exon 7 of 9	ENST00000373960.4	NP_001918.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DES	ENST00000373960.4	c.1255_1271delCCCATCCAGACCTACTC	p.Pro419CysfsTer10	frameshift_variant	Exon 7 of 9	1	NM_001927.4	ENSP00000363071.3
DES	ENST00000477226.6	n.729_745delCCCATCCAGACCTACTC		non_coding_transcript_exon_variant	Exon 6 of 8	4
DES	ENST00000492726.1	n.650_666delCCCATCCAGACCTACTC		non_coding_transcript_exon_variant	Exon 6 of 6	4
DES	ENST00000683013.1	n.643_659delCCCATCCAGACCTACTC		non_coding_transcript_exon_variant	Exon 5 of 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

Jan 31, 2017

Undiagnosed Diseases Network, NIH

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jun 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.7
Mutation Taster		=3/197	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs1553603732; hg19: chr2-220288505;