rs140871298
Positions:
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP2PP3BS2
The NM_006258.4(PRKG1):āc.395A>Gā(p.Asp132Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000229 in 1,612,466 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 Uncertain significance (ā ā ).
Frequency
Genomes: š 0.000013 ( 0 hom., cov: 31)
Exomes š: 0.000024 ( 0 hom. )
Consequence
PRKG1
NM_006258.4 missense
NM_006258.4 missense
Scores
10
6
1
Clinical Significance
Conservation
PhyloP100: 8.64
Genes affected
PRKG1 (HGNC:9414): (protein kinase cGMP-dependent 1) Mammals have three different isoforms of cyclic GMP-dependent protein kinase (Ialpha, Ibeta, and II). These PRKG isoforms act as key mediators of the nitric oxide/cGMP signaling pathway and are important components of many signal transduction processes in diverse cell types. This PRKG1 gene on human chromosome 10 encodes the soluble Ialpha and Ibeta isoforms of PRKG by alternative transcript splicing. A separate gene on human chromosome 4, PRKG2, encodes the membrane-bound PRKG isoform II. The PRKG1 proteins play a central role in regulating cardiovascular and neuronal functions in addition to relaxing smooth muscle tone, preventing platelet aggregation, and modulating cell growth. This gene is most strongly expressed in all types of smooth muscle, platelets, cerebellar Purkinje cells, hippocampal neurons, and the lateral amygdala. Isoforms Ialpha and Ibeta have identical cGMP-binding and catalytic domains but differ in their leucine/isoleucine zipper and autoinhibitory sequences and therefore differ in their dimerization substrates and kinase enzyme activity. [provided by RefSeq, Sep 2011]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -2 ACMG points.
PP2
?
Missense variant where missense usually causes diseases, PRKG1
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.772
BS2
?
High AC in GnomAdExome4 at 35 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PRKG1 | NM_006258.4 | c.395A>G | p.Asp132Gly | missense_variant | 2/18 | ENST00000373980.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PRKG1 | ENST00000373980.11 | c.395A>G | p.Asp132Gly | missense_variant | 2/18 | 1 | NM_006258.4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000132 AC: 2AN: 151932Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.0000359 AC: 9AN: 250968Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135658
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GnomAD4 exome AF: 0.0000240 AC: 35AN: 1460534Hom.: 0 Cov.: 30 AF XY: 0.0000234 AC XY: 17AN XY: 726580
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GnomAD4 genome ? AF: 0.0000132 AC: 2AN: 151932Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74202
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Familial thoracic aortic aneurysm and aortic dissection Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 28, 2022 | The p.D132G variant (also known as c.395A>G), located in coding exon 2 of the PRKG1 gene, results from an A to G substitution at nucleotide position 395. The aspartic acid at codon 132 is replaced by glycine, an amino acid with similar properties. 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 16, 2018 | A variant of uncertain significance has been identified in the PRKG1 gene. The D132G variant has not been published as pathogenic or been reported as benign to our knowledge. This variant has been observed in 1/10402 (0.010%) alleles from individuals of African ancestry, 1/11404 (0.009%) alleles from individuals of Latino ancestry, and 5/66650 (0.008%) alleles from individuals of Non-Finnish European ancestry, in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The D132G variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Additionally, this substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Nevertheless, this variant has not been observed in a significant number of affected individuals, and it lacks both segregation and functional studies which would further clarify its pathogenicity. - |
Aortic aneurysm, familial thoracic 8 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 19, 2022 | This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 132 of the PRKG1 protein (p.Asp132Gly). This variant is present in population databases (rs140871298, gnomAD 0.006%). 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: 451745). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
D;D;.;.;.;.;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
M;M;.;.;.;.;.;.
MutationTaster
Benign
D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;.;.;.;D;.;.;.
REVEL
Pathogenic
Sift
Uncertain
D;.;.;.;D;.;.;.
Polyphen
B;B;.;B;B;.;.;.
Vest4
0.89, 0.88
MVP
0.95
MPC
1.0
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at