10-52251599-A-G
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2
The NM_006258.4(PRKG1):c.1106A>G(p.Asn369Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000465 in 1,613,496 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_006258.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152154Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000319 AC: 8AN: 251040Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135668
GnomAD4 exome AF: 0.0000506 AC: 74AN: 1461342Hom.: 0 Cov.: 30 AF XY: 0.0000454 AC XY: 33AN XY: 726980
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152154Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74316
ClinVar
Submissions by phenotype
not specified Uncertain:1
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Familial thoracic aortic aneurysm and aortic dissection Uncertain:1
The p.N369S variant (also known as c.1106A>G), located in coding exon 10 of the PRKG1 gene, results from an A to G substitution at nucleotide position 1106. The asparagine at codon 369 is replaced by serine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species; however, serine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. In addition, this alteration is predicted to create a new alternate splice acceptor site by the BDGP and ESE finder in silico models; however experimental evidence is not available. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Aortic aneurysm, familial thoracic 8 Uncertain:1
This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 369 of the PRKG1 protein (p.Asn369Ser). This variant is present in population databases (rs775372704, gnomAD 0.009%). This variant has not been reported in the literature in individuals affected with PRKG1-related conditions. ClinVar contains an entry for this variant (Variation ID: 451057). 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 tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
not provided Uncertain:1
A variant of uncertain significance has been identified in the PRKG1 gene. The N369S variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Nevertheless, the N369S variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Additionally, this substitution occurs at a position not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at