2-219425727-C-T
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Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM2BP4_StrongBP6BP7BS1
The ENST00000373960.4(DES):c.1353C>T(p.Ile451=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000139 in 1,602,978 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00025 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00013 ( 1 hom. )
Consequence
DES
ENST00000373960.4 synonymous
ENST00000373960.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -2.88
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]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -8 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.52).
BP6
Variant 2-219425727-C-T is Benign according to our data. Variant chr2-219425727-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 226559.We mark this variant Likely_benign, oryginal submissions are: {Benign=4, Uncertain_significance=1, Likely_benign=1}. Variant chr2-219425727-C-T is described in Lovd as [Benign]. Variant chr2-219425727-C-T is described in Lovd as [Likely_benign].
BP7
Synonymous conserved (PhyloP=-2.88 with no splicing effect.
BS1
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00025 (38/152044) while in subpopulation EAS AF= 0.00601 (31/5156). AF 95% confidence interval is 0.00435. There are 0 homozygotes in gnomad4. There are 19 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
DES | NM_001927.4 | c.1353C>T | p.Ile451= | synonymous_variant | 8/9 | ENST00000373960.4 | NP_001918.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DES | ENST00000373960.4 | c.1353C>T | p.Ile451= | synonymous_variant | 8/9 | 1 | NM_001927.4 | ENSP00000363071 | P1 | |
ENST00000431827.1 | n.104+354G>A | intron_variant, non_coding_transcript_variant | 5 |
Frequencies
GnomAD3 genomes AF: 0.000250 AC: 38AN: 151926Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000564 AC: 131AN: 232466Hom.: 1 AF XY: 0.000528 AC XY: 66AN XY: 125040
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GnomAD4 exome AF: 0.000128 AC: 185AN: 1450934Hom.: 1 Cov.: 31 AF XY: 0.000129 AC XY: 93AN XY: 720560
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GnomAD4 genome AF: 0.000250 AC: 38AN: 152044Hom.: 0 Cov.: 32 AF XY: 0.000256 AC XY: 19AN XY: 74326
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:7
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:1Benign:2
Benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 03, 2015 | - - |
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Sep 10, 2015 | - - |
not specified Benign:2
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Oct 01, 2015 | p.Ile451Ile in exon 8 of DES:This variant is not expected to have clinical signi ficance because it does not alter an amino acid residue and is not located withi n the splice consensus sequence. It has been identified in 1.1% (43/3920) of Eas t Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broad institute.org; dbSNP rs121913002). - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Desmin-related myofibrillar myopathy Benign:1
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 24, 2024 | - - |
Cardiomyopathy Benign:1
Benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | May 03, 2021 | - - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 10, 2017 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
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Name
Calibrated prediction
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at