chr6-7566429-A-G
Variant summary
Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4BP6
The NM_004415.4(DSP):c.992A>G(p.Gln331Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,754 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. Q331P) has been classified as Uncertain significance.
Frequency
Consequence
NM_004415.4 missense
Scores
Clinical Significance
Conservation
Publications
- arrhythmogenic right ventricular dysplasia 8Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
- keratosis palmoplantaris striata 2Inheritance: AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: G2P, Ambry Genetics, Genomics England PanelApp
- skin fragility-woolly hair-palmoplantar keratoderma syndromeInheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, G2P, Genomics England PanelApp, Ambry Genetics
- arrhythmogenic cardiomyopathy with wooly hair and keratodermaInheritance: AR, AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, ClinGen, Orphanet, Ambry Genetics
- cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesisInheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
- lethal acantholytic epidermolysis bullosaInheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet
- familial isolated dilated cardiomyopathyInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- striate palmoplantar keratodermaInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- severe dermatitis-multiple allergies-metabolic wasting syndromeInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- hypertrophic cardiomyopathyInheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
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ACMG classification
Our verdict: Uncertain_significance. The variant received 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
DSP | NM_004415.4 | c.992A>G | p.Gln331Arg | missense_variant | Exon 8 of 24 | ENST00000379802.8 | NP_004406.2 | |
DSP | NM_001319034.2 | c.992A>G | p.Gln331Arg | missense_variant | Exon 8 of 24 | NP_001305963.1 | ||
DSP | NM_001008844.3 | c.992A>G | p.Gln331Arg | missense_variant | Exon 8 of 24 | NP_001008844.1 | ||
DSP | NM_001406591.1 | c.992A>G | p.Gln331Arg | missense_variant | Exon 8 of 11 | NP_001393520.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD2 exomes AF: 0.00000796 AC: 2AN: 251124 AF XY: 0.00 show subpopulations
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461754Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727186 show subpopulations
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Cardiomyopathy Uncertain:1
This missense variant replaces glutamine with arginine at codon 331 of the DSP protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 2/251124 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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. -
Cardiovascular phenotype Uncertain:1
The p.Q331R variant (also known as c.992A>G), located in coding exon 8 of the DSP gene, results from an A to G substitution at nucleotide position 992. The glutamine at codon 331 is replaced by arginine, an amino acid with highly similar properties. This alteration has been reported in a congenital heart defect cohort in a fetus with an additional alteration in DSP identified in trans (Sun S et al. Front Genet, 2024 Aug;15:1448383). This amino acid position is well 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 variant remains unclear. -
Arrhythmogenic right ventricular dysplasia 8;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at