rs1554833919

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP2BP4

The ENST00000373980.11(PRKG1):​c.298C>T​(p.Pro100Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P100R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

PRKG1
ENST00000373980.11 missense

Scores

1
2
13

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 5.48
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
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.
BP4
Computational evidence support a benign effect (MetaRNN=0.29272157).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PRKG1NM_006258.4 linkuse as main transcriptc.298C>T p.Pro100Ser missense_variant 1/18 ENST00000373980.11 NP_006249.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PRKG1ENST00000373980.11 linkuse as main transcriptc.298C>T p.Pro100Ser missense_variant 1/181 NM_006258.4 ENSP00000363092 Q13976-2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
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 submitterclinical testingAmbry GeneticsSep 26, 2023The p.P100S variant (also known as c.298C>T), located in coding exon 1 of the PRKG1 gene, results from a C to T substitution at nucleotide position 298. The proline at codon 100 is replaced by serine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Connective tissue disorder Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingCenter for Human Genetics, Inc, Center for Human Genetics, IncNov 01, 2016- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Uncertain
0.092
D
BayesDel_noAF
Benign
-0.11
CADD
Uncertain
24
DANN
Benign
0.97
Eigen
Benign
-0.027
Eigen_PC
Benign
0.18
FATHMM_MKL
Benign
0.74
D
LIST_S2
Benign
0.85
D;.;T;D;D;D
M_CAP
Benign
0.052
D
MetaRNN
Benign
0.29
T;T;T;T;T;T
MetaSVM
Benign
-0.43
T
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Pathogenic
0.82
D
PROVEAN
Benign
-1.5
.;.;N;.;.;.
REVEL
Uncertain
0.30
Sift
Benign
0.50
.;.;T;.;.;.
Sift4G
Benign
0.56
.;.;T;.;.;.
Polyphen
0.0040
.;B;B;.;.;.
Vest4
0.29
MutPred
0.26
Loss of glycosylation at P100 (P = 0.0255);Loss of glycosylation at P100 (P = 0.0255);Loss of glycosylation at P100 (P = 0.0255);Loss of glycosylation at P100 (P = 0.0255);Loss of glycosylation at P100 (P = 0.0255);Loss of glycosylation at P100 (P = 0.0255);
MVP
0.62
MPC
0.65
ClinPred
0.98
D
GERP RS
5.5
gMVP
0.79

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.11
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1554833919; hg19: chr10-52834648; API