rs774514264
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PVS1PP3PP5_Very_Strong
The NM_004415.4(DSP):c.2436+2T>C variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000867 in 1,614,054 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 (★★).
Frequency
Consequence
NM_004415.4 splice_donor
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 17 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DSP | NM_004415.4 | c.2436+2T>C | splice_donor_variant | ENST00000379802.8 | |||
DSP | NM_001008844.3 | c.2436+2T>C | splice_donor_variant | ||||
DSP | NM_001319034.2 | c.2436+2T>C | splice_donor_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DSP | ENST00000379802.8 | c.2436+2T>C | splice_donor_variant | 1 | NM_004415.4 | P2 | |||
DSP | ENST00000418664.2 | c.2436+2T>C | splice_donor_variant | 1 | A2 | ||||
DSP | ENST00000710359.1 | c.2436+2T>C | splice_donor_variant | A2 | |||||
DSP | ENST00000684395.1 | n.1077+2T>C | splice_donor_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152198Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251420Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135880
GnomAD4 exome AF: 0.00000821 AC: 12AN: 1461856Hom.: 0 Cov.: 32 AF XY: 0.00000963 AC XY: 7AN XY: 727230
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152198Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74354
ClinVar
Submissions by phenotype
Cardiomyopathy Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jun 22, 2023 | This variant causes a T to C nucleotide substitution at the +2 position of intron 17 of the DSP gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in one individual affected with dilated cardiomyopathy (PMID: 29892087), and in several individuals from population-based cohorts whose clinical information were limited (PMID: 31447099, 31589614, 33684294). This variant has been identified in 1/251420 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of DSP function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Mar 24, 2023 | - - |
Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jan 08, 2024 | This variant causes a T to C nucleotide substitution at the +2 position of intron 17 of the DSP gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in one individual affected with dilated cardiomyopathy (PMID: 29892087), and in several individuals from population-based cohorts whose clinical information were limited (PMID: 31447099, 31589614, 33684294). This variant has been identified in 1/251420 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of DSP function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic. - |
Arrhythmogenic right ventricular dysplasia 8;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Apr 14, 2023 | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 388661). Disruption of this splice site has been observed in individual(s) with dilated cardiomyopathy (PMID: 29892087). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 17 of the DSP gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in DSP are known to be pathogenic (PMID: 20716751, 24503780, 25227139). - |
Arrhythmogenic right ventricular cardiomyopathy Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 17, 2019 | The c.2436+2T>C variant in DSP has not been previously reported in the literatur e in individuals with cardiomyopathy, but has been reported by other clinical la boratories in ClinVar (Variation ID: 388661). It has also been identified in 1/6 6720 European chromosomes by the Genome Aggregation Database (gnomAD, http://gno mad.broadinstitute.org/; dbSNP rs774514264). This variant occurs in the invarian t region (+/- 1,2) of the splice consensus sequence and is predicted to cause al tered splicing leading to an abnormal or absent protein, which is common among d isease causing DSP variants. In summary, although additional studies are require d to fully establish its clinical significance, the c.2436+2T>C variant is likel y pathogenic. - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 06, 2023 | Identified in a patient with DCM in published literature, but familial segregation information and additional clinical information were not included (Horvat et al., 2019); Not observed at a significant frequency in large population cohorts (gnomAD); Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 31447099, 31589614, 31402444, 33684294, 33087929, 29892087) - |
Arrhythmogenic right ventricular dysplasia 8 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine | Aug 23, 2022 | The c.2436+2T>C variant of the DSP gene impacts the splice donor site in intron 7. It is predicted to disrupt RNA splicing. Variants that disrupt the splice site typically lead to loss of protein function. Variants leading to loss of function in DSP have been shown to be pathogenic (PMID: 20716751, 24503780, 25227139). This variant has been reported in individuals with or at risk for cardiomyopathy (PMID: 33684294, 29892087). The frequency of this variant in the general population database (gnomAD) is rare (1/25142). ClinVar contains an entry for this variant (Variation ID: 388661). Based on the available evidence, this variant is classified as likely pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at