rs606231377
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 8P and 9B. PVS1BP6BA1
The NM_004415.4(DSP):c.1dupA(p.Met1fs) variant causes a frameshift, start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.148 in 1,609,250 control chromosomes in the GnomAD database, including 19,165 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_004415.4 frameshift, start_lost
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.173 AC: 26256AN: 152080Hom.: 2450 Cov.: 30
GnomAD3 exomes AF: 0.167 AC: 38677AN: 231420Hom.: 3569 AF XY: 0.161 AC XY: 20455AN XY: 127368
GnomAD4 exome AF: 0.146 AC: 212018AN: 1457052Hom.: 16712 Cov.: 32 AF XY: 0.144 AC XY: 104253AN XY: 724520
GnomAD4 genome AF: 0.173 AC: 26267AN: 152198Hom.: 2453 Cov.: 30 AF XY: 0.175 AC XY: 13040AN XY: 74410
ClinVar
Submissions by phenotype
not specified Benign:9
The variant has been reported in dbSNP without frequency information (rs17133512 ). Classified as benign based on high allele frequency (0.162, n=290 chromosomes ) in ARVC probands tested at the LMM. In addition, the fraction of probands carr ying the -1_1insA variant matches the expected detection rate for ARVC (~50%), f urther supporting a benign role. -
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Variant summary: DSP c.1dupA is located in the untranslated mRNA region upstream of the initiation codon. The variant allele was found at a frequency of 0.17 in 231420 control chromosomes in the gnomAD database, including 3569 homozygotes. The observed variant frequency is approximately 6685.078 fold of the estimated maximal expected allele frequency for a pathogenic variant in DSP causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is benign. c.1dupA has been reported in the literature in individuals affected with Cardiomyopathy. These report(s) do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -
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This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
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Cardiomyopathy Benign:2
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Arrhythmogenic right ventricular dysplasia 8 Uncertain:1
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Arrhythmogenic right ventricular cardiomyopathy Benign:1
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Lethal acantholytic epidermolysis bullosa Benign:1
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Woolly hair-skin fragility syndrome Benign:1
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Cardiovascular phenotype Benign:1
Internal frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at