rs775427696
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Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP2PP3BS2
The NM_006258.4(PRKG1):c.449A>C(p.Asp150Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000316 in 1,611,572 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 (★★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000034 ( 0 hom. )
Consequence
PRKG1
NM_006258.4 missense
NM_006258.4 missense
Scores
10
5
4
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 in gene, where missense usually causes diseases (based on misZ statistic), PRKG1. . Gene score misZ 2.982 (greater than the threshold 3.09). Trascript score misZ 3.8719 (greater than threshold 3.09). GenCC has associacion of gene with familial thoracic aortic aneurysm and aortic dissection, aortic aneurysm, familial thoracic 8.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.834
BS2
High AC in GnomAdExome4 at 49 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PRKG1 | NM_006258.4 | c.449A>C | p.Asp150Ala | missense_variant | 2/18 | ENST00000373980.11 | NP_006249.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PRKG1 | ENST00000373980.11 | c.449A>C | p.Asp150Ala | missense_variant | 2/18 | 1 | NM_006258.4 | ENSP00000363092.5 |
Frequencies
GnomAD3 genomes AF: 0.0000132 AC: 2AN: 151946Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.0000240 AC: 6AN: 249962Hom.: 0 AF XY: 0.0000222 AC XY: 3AN XY: 135108
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GnomAD4 exome AF: 0.0000336 AC: 49AN: 1459626Hom.: 0 Cov.: 30 AF XY: 0.0000331 AC XY: 24AN XY: 726124
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GnomAD4 genome AF: 0.0000132 AC: 2AN: 151946Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74210
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Aortic aneurysm, familial thoracic 8 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 17, 2023 | This sequence change replaces aspartic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 150 of the PRKG1 protein (p.Asp150Ala). This variant is present in population databases (rs775427696, gnomAD 0.007%). This missense change has been observed in individual(s) with clinical features of PRKG1-related conditions (PMID: 29907982). This variant is also known as c.404A>C, p.Asp135Ala. ClinVar contains an entry for this variant (Variation ID: 544057). 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
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jan 26, 2023 | Identified in a patient with thoracic aortic aneurysm and aortic dissection (TAAD) (Overwater et al., 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29907982) - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Pathogenic
D;D;.;.;.;.;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
.;D;D;.;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Benign
L;L;.;.;.;.;.;.
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;.;.;.;D;.;.;D
REVEL
Pathogenic
Sift
Benign
T;.;.;.;T;.;.;T
Sift4G
Benign
.;T;.;.;T;.;.;.
Polyphen
B;B;.;B;B;.;.;.
Vest4
0.89, 0.86
MVP
0.95
MPC
0.96
ClinPred
T
GERP RS
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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