NM_004415.4:c.6442G>A
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate
The NM_004415.4(DSP):c.6442G>A(p.Ala2148Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000192 in 1,613,972 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_004415.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
DSP | NM_004415.4 | c.6442G>A | p.Ala2148Thr | missense_variant | Exon 24 of 24 | ENST00000379802.8 | NP_004406.2 | |
DSP | NM_001319034.2 | c.5113G>A | p.Ala1705Thr | missense_variant | Exon 24 of 24 | NP_001305963.1 | ||
DSP | NM_001008844.3 | c.4645G>A | p.Ala1549Thr | missense_variant | Exon 24 of 24 | NP_001008844.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DSP | ENST00000379802.8 | c.6442G>A | p.Ala2148Thr | missense_variant | Exon 24 of 24 | 1 | NM_004415.4 | ENSP00000369129.3 | ||
DSP | ENST00000418664.2 | c.4645G>A | p.Ala1549Thr | missense_variant | Exon 24 of 24 | 1 | ENSP00000396591.2 | |||
DSP | ENST00000710359.1 | c.5113G>A | p.Ala1705Thr | missense_variant | Exon 24 of 24 | ENSP00000518230.1 |
Frequencies
GnomAD3 genomes AF: 0.0000394 AC: 6AN: 152100Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251238Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135814
GnomAD4 exome AF: 0.0000171 AC: 25AN: 1461872Hom.: 0 Cov.: 32 AF XY: 0.0000165 AC XY: 12AN XY: 727234
GnomAD4 genome AF: 0.0000394 AC: 6AN: 152100Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74304
ClinVar
Submissions by phenotype
not provided Uncertain:3
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not specified Uncertain:1
The p.Ala2148Thr variant in DSP has not been previously reported in patients wit h cardiomyopathy but has been identified in 1/16484 of South Asian chromosomes a nd 1/10288 African chromosomes by the Exome Aggregation Consortium (ExAC, http:/ /exac.broadinstitute.org; rs144539278). Computational prediction tools and conse rvation analysis suggest that this variant may impact the protein, though this i nformation is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Ala2148Thr variant is uncertain. -
Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Uncertain:1
This missense variant replaces alanine with threonine at codon 2148 of the DSP protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with arrhythmogenic right ventricular cardiomyopathy who also carried a pathogenic variant in the DSP gene (PMID: 31319917), in an individual affected with an unspecified cardiomyopathy with clinical limited details (PMID: 37477868), and in an individual affected with alcoholic cardiomyopathy (PMID: 29773157). This variant has been identified in 6/282610 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. -
Cardiomyopathy Uncertain:1
This missense variant replaces alanine with threonine at codon 2148 of the DSP protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with arrhythmogenic right ventricular cardiomyopathy who also carried a pathogenic variant in the DSP gene (PMID: 31319917), in an individual affected with an unspecified cardiomyopathy with clinical limited details (PMID: 37477868), and in an individual affected with alcoholic cardiomyopathy (PMID: 29773157). This variant has been identified in 6/282610 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. -
Cardiovascular phenotype Uncertain:1
The p.A2148T variant (also known as c.6442G>A), located in coding exon 24 of the DSP gene, results from a G to A substitution at nucleotide position 6442. The alanine at codon 2148 is replaced by threonine, an amino acid with similar properties. This variant has been detected in individuals from unspecified cardiomyopathy and alcohol-induced cardiomyopathy cohorts and co-occurred with a DSP nonsense mutation in a proband with arrhythmogenic right ventricular cardiomyopathy (Ware JS et al. J Am Coll Cardiol, 2018 May;71:2293-2302; DeWitt ES et al. J Am Coll Cardiol, 2019 Jul;74:346-358; Akinrinade O et al. J Cardiovasc Transl Res, 2023 Jul). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration 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