rs143154982
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Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6BP7
The NM_001927.4(DES):c.1257C>T(p.Pro419=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,613,766 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.000099 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0000075 ( 0 hom. )
Consequence
DES
NM_001927.4 synonymous
NM_001927.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -2.00
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 Likely_benign. Variant got -4 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.83).
BP6
Variant 2-219423789-C-T is Benign according to our data. Variant chr2-219423789-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 384758.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=5}.
BP7
Synonymous conserved (PhyloP=-2 with no splicing effect.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DES | NM_001927.4 | c.1257C>T | p.Pro419= | synonymous_variant | 7/9 | ENST00000373960.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DES | ENST00000373960.4 | c.1257C>T | p.Pro419= | synonymous_variant | 7/9 | 1 | NM_001927.4 | P1 | |
DES | ENST00000477226.6 | n.731C>T | non_coding_transcript_exon_variant | 6/8 | 4 | ||||
DES | ENST00000492726.1 | n.652C>T | non_coding_transcript_exon_variant | 6/6 | 4 | ||||
DES | ENST00000683013.1 | n.645C>T | non_coding_transcript_exon_variant | 5/7 |
Frequencies
GnomAD3 genomes AF: 0.0000986 AC: 15AN: 152134Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.0000517 AC: 13AN: 251492Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135922
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GnomAD4 exome AF: 0.00000753 AC: 11AN: 1461632Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6AN XY: 727118
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GnomAD4 genome AF: 0.0000986 AC: 15AN: 152134Hom.: 0 Cov.: 31 AF XY: 0.000108 AC XY: 8AN XY: 74294
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:5
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Dec 27, 2016 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | May 06, 2019 | - - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Aug 17, 2016 | - - |
Desmin-related myofibrillar myopathy Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 01, 2024 | - - |
DES-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 19, 2023 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | May 09, 2018 | 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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BayesDel_noAF
Benign
CADD
Benign
DANN
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Splicing
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at