rs528041468
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP6_Moderate
The NM_004415.4(DSP):c.5353G>A(p.Glu1785Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,613,872 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Synonymous variant affecting the same amino acid position (i.e. E1785E) has been classified as Likely benign.
Frequency
Consequence
NM_004415.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DSP | NM_004415.4 | c.5353G>A | p.Glu1785Lys | missense_variant | 23/24 | ENST00000379802.8 | |
DSP | NM_001008844.3 | c.3583-1099G>A | intron_variant | ||||
DSP | NM_001319034.2 | c.4051-1099G>A | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DSP | ENST00000379802.8 | c.5353G>A | p.Glu1785Lys | missense_variant | 23/24 | 1 | NM_004415.4 | P2 | |
DSP | ENST00000418664.2 | c.3583-1099G>A | intron_variant | 1 | A2 | ||||
DSP | ENST00000710359.1 | c.4051-1099G>A | intron_variant | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152174Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000401 AC: 1AN: 249134Hom.: 0 AF XY: 0.00000739 AC XY: 1AN XY: 135252
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461580Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3AN XY: 727084
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152292Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74478
ClinVar
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, no assertion criteria provided | provider interpretation | Stanford Center for Inherited Cardiovascular Disease, Stanford University | May 16, 2017 | p.Glu1785Lys (c.5353G>A) in exon 23 of the DSP gene (NM_004415.2; chr6-7581776-G-A) Given that this variant has not been reported in the literature, the frequency of missense variation in DSP in controls, and its rarity in population databases, we consider this variant a variant of uncertain significance and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). This variant has not been reported in the literature. Kapplinger et al. (2011) from Michael Ackerman’s group have reported a significant yield of rare missense variants in the ARVC genes of presumably healthy controls from various ethnicities. According to their data, 16% of 427 controls hosted missense variants—similar to the 21% yield in 175 Dutch and U.S. ARVC cases. This is a reminder that missense variants of unknown significance in ARVC-related genes need to be interpreted with caution. Kapplinger et al. also report a “hot spot†for DSP variants between amino acids 250-604 in patients with ARVC but not in controls. Walsh et al (2016) found that truncating DSP variants were enriched in cases of DCM over ExAC controls with odds ration of 41.0. There was not significant enrichment of DSP missense variants in DCM cases. DSP truncating variants were also enriched in ARVC cases vs. ExAC controls with odds ratio of 89.9. DSP missense variants were only slightly enriched in cases of ARVC vs. ExAC controls with odds ratio of 2.1. According to the test report, "algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). The glutamic acid at codon 1785 is conserved across species, as are neighboring amino acids. No other variants at this codon or around this codon have been associated with disease. The variant was reported online in 1 of 122,361 individuals in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. Specifically, the variant was observed in 1 of 15,357 individuals of South Asian descent (MAF=0.003%). The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. - |
Arrhythmogenic right ventricular dysplasia 8;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Dec 06, 2022 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at