chr2-219425746-G-A
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1PM2PP3_Strong
The NM_001927.4(DES):c.1371+1G>A variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000243 in 1,605,818 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001927.4 splice_donor
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.1371+1G>A | splice_donor_variant | ENST00000373960.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DES | ENST00000373960.4 | c.1371+1G>A | splice_donor_variant | 1 | NM_001927.4 | P1 | |||
ENST00000431827.1 | n.104+335C>T | intron_variant, non_coding_transcript_variant | 5 |
Frequencies
GnomAD3 genomes AF: 0.0000461 AC: 7AN: 152008Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000339 AC: 8AN: 235836Hom.: 0 AF XY: 0.0000394 AC XY: 5AN XY: 127010
GnomAD4 exome AF: 0.0000220 AC: 32AN: 1453810Hom.: 0 Cov.: 31 AF XY: 0.0000249 AC XY: 18AN XY: 722336
GnomAD4 genome AF: 0.0000461 AC: 7AN: 152008Hom.: 0 Cov.: 32 AF XY: 0.0000539 AC XY: 4AN XY: 74246
ClinVar
Submissions by phenotype
not provided Pathogenic:1Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | AiLife Diagnostics, AiLife Diagnostics | Mar 09, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 03, 2023 | Canonical splice site variant with an unclear effect on protein function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 26582918) - |
not specified Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Stanford Center for Inherited Cardiovascular Disease, Stanford University | Jan 18, 2013 | Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease - |
Desmin-related myofibrillar myopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 03, 2022 | This sequence change affects a donor splice site in intron 8 of the DES gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is present in population databases (rs748323823, gnomAD 0.07%). Disruption of this splice site has been observed in individual(s) with clinical features of autosomal dominant dilated cardiomyopathy (Invitae). ClinVar contains an entry for this variant (Variation ID: 201714). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 11, 2023 | The c.1371+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 8 of the DES gene. This alteration disrupts the highly conserved canonical splice donor site and is expected to cause aberrant splicing. Internal RNA studies indicate that this alteration leads to the utilization of a cryptic donor site seven nucleotides downstream of the canonical splice donor site, causing a translational frameshift with a predicted alternate stop codon (p.V459Sfs*5) (Ambry internal data). Frameshifts are typically deleterious in nature; however, this frameshift occurs at the 3' terminus of DES, is not expected to trigger nonsense-mediated mRNA decay, and impacts only the last 12 amino acids of the protein. The exact functional impact of these altered amino acids is unknown at this time. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at