rs387906618
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PM5PP3_ModeratePP5_Very_Strong
The NM_004415.4(DSP):c.7097G>A(p.Arg2366His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,864 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2366C) has been classified as Likely pathogenic.
Frequency
Consequence
NM_004415.4 missense
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 |
---|---|---|---|---|---|---|---|
DSP | NM_004415.4 | c.7097G>A | p.Arg2366His | missense_variant | 24/24 | ENST00000379802.8 | |
DSP | NM_001319034.2 | c.5768G>A | p.Arg1923His | missense_variant | 24/24 | ||
DSP | NM_001008844.3 | c.5300G>A | p.Arg1767His | missense_variant | 24/24 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DSP | ENST00000379802.8 | c.7097G>A | p.Arg2366His | missense_variant | 24/24 | 1 | NM_004415.4 | P2 | |
DSP | ENST00000418664.2 | c.5300G>A | p.Arg1767His | missense_variant | 24/24 | 1 | A2 | ||
DSP | ENST00000710359.1 | c.5768G>A | p.Arg1923His | missense_variant | 24/24 | A2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251390Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135868
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461864Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727228
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Jan 15, 2024 | Criteria applied: PP1_STR,PM3,PM5,PM2_SUP,PP3,PP4 - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 01, 2011 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine | Oct 04, 2023 | - - |
Likely pathogenic, criteria provided, single submitter | research | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 17, 2024 | - - |
Arrhythmogenic right ventricular dysplasia 8;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 11, 2023 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 2366 of the DSP protein (p.Arg2366His). This variant is present in population databases (rs387906618, gnomAD 0.003%). This missense change has been observed in individual(s) with autosomal recessive skin fragility–woolly hair syndrome (PMID: 20738328). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 29672). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This variant disrupts the p.Arg2366 amino acid residue in DSP. Other variant(s) that disrupt this residue have been observed in individuals with DSP-related conditions (PMID: 11841538), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at