6-7575480-C-G
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.
The NM_004415.4(DSP):āc.2622C>Gā(p.Ile874Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000483 in 1,614,004 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I874F) has been classified as Uncertain significance.
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.2622C>G | p.Ile874Met | missense_variant | 18/24 | ENST00000379802.8 | |
DSP | NM_001319034.2 | c.2622C>G | p.Ile874Met | missense_variant | 18/24 | ||
DSP | NM_001008844.3 | c.2622C>G | p.Ile874Met | missense_variant | 18/24 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DSP | ENST00000379802.8 | c.2622C>G | p.Ile874Met | missense_variant | 18/24 | 1 | NM_004415.4 | P2 | |
DSP | ENST00000418664.2 | c.2622C>G | p.Ile874Met | missense_variant | 18/24 | 1 | A2 | ||
DSP | ENST00000710359.1 | c.2622C>G | p.Ile874Met | missense_variant | 18/24 | A2 | |||
DSP | ENST00000684395.1 | n.1263C>G | non_coding_transcript_exon_variant | 5/5 |
Frequencies
GnomAD3 genomes AF: 0.0000394 AC: 6AN: 152174Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000438 AC: 11AN: 251112Hom.: 0 AF XY: 0.0000515 AC XY: 7AN XY: 135798
GnomAD4 exome AF: 0.0000493 AC: 72AN: 1461830Hom.: 1 Cov.: 34 AF XY: 0.0000523 AC XY: 38AN XY: 727222
GnomAD4 genome AF: 0.0000394 AC: 6AN: 152174Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4AN XY: 74336
ClinVar
Submissions by phenotype
Cardiomyopathy Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Dec 07, 2016 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Feb 16, 2023 | This missense variant replaces isoleucine with methionine at codon 874 of the DSP protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 12/282506 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 18, 2023 | This missense variant replaces isoleucine with methionine at codon 874 of the DSP protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 12/282506 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 24, 2023 | Identified in a patient with DCM in published literature (Pena-Pena et al., 2021); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32826072) - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 20, 2024 | The p.I874M variant (also known as c.2622C>G), located in coding exon 18 of the DSP gene, results from a C to G substitution at nucleotide position 2622. The isoleucine at codon 874 is replaced by methionine, an amino acid with highly similar properties. This variant has been reported in association with dilated cardiomyopathy (DCM) (Peña-Peña ML et al. Med Clin (Barc), 2021 May;156:485-495). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this alteration remains unclear. - |
Woolly hair-skin fragility syndrome;C1843896:Arrhythmogenic right ventricular dysplasia 8;C1852127:Keratosis palmoplantaris striata 2;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma;C1864826:Lethal acantholytic epidermolysis bullosa;C4014393:Cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 28, 2021 | - - |
Arrhythmogenic right ventricular dysplasia 8;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 09, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at