2-219420346-G-C
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_001927.4(DES):c.735G>C(p.Glu245Asp) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin Lovd. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E245G) has been classified as Uncertain significance.
Frequency
Consequence
NM_001927.4 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DES | NM_001927.4 | c.735G>C | p.Glu245Asp | missense_variant, splice_region_variant | 3/9 | ENST00000373960.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DES | ENST00000373960.4 | c.735G>C | p.Glu245Asp | missense_variant, splice_region_variant | 3/9 | 1 | NM_001927.4 | P1 | |
DES | ENST00000477226.6 | n.209G>C | splice_region_variant, non_coding_transcript_exon_variant | 2/8 | 4 | ||||
DES | ENST00000492726.1 | n.130G>C | splice_region_variant, non_coding_transcript_exon_variant | 2/6 | 4 | ||||
DES | ENST00000683013.1 | n.123G>C | splice_region_variant, non_coding_transcript_exon_variant | 1/7 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 35
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:1Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Mar 10, 2016 | - - |
not provided, no classification provided | literature only | Epithelial Biology; Institute of Medical Biology, Singapore | - | - - |
Desmin-related myofibrillar myopathy Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The missense variant p.E245D in DES (NM_001927.4) has been previously reported in heterozygous state in affected patients (Vrabie A et al, 2005). The p.E245D variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The p.E245D variant is present at the splice site and is predicted to disrupt splicing by all splice site algorithms. The p.E245D missense variant is predicted to be damaging by both SIFT and PolyPhen2. The glutamic acid residue at codon 245 of DES is conserved in all mammalian species. The nucleotide c.735 in DES is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic - |
Dilated cardiomyopathy 1I Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Mar 14, 2022 | _x000D_ Criteria applied: PVS1_STR, PS3_SUP, PS4_SUP, PM2_SUP, PP3 - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at