10-52280851-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP2PP3_Strong

The NM_006258.4(PRKG1):ā€‹c.1466A>Gā€‹(p.Tyr489Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,214 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˜…). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y489F) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 0.0000014 ( 0 hom. )

Consequence

PRKG1
NM_006258.4 missense

Scores

12
6
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.28
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]
PRKG1-AS1 (HGNC:45029): (PRKG1 antisense RNA 1)

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 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.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.975

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PRKG1NM_006258.4 linkuse as main transcriptc.1466A>G p.Tyr489Cys missense_variant 13/18 ENST00000373980.11
PRKG1NM_001098512.3 linkuse as main transcriptc.1421A>G p.Tyr474Cys missense_variant 13/18
PRKG1NM_001374781.1 linkuse as main transcriptc.257A>G p.Tyr86Cys missense_variant 9/14
PRKG1XM_017016413.2 linkuse as main transcriptc.1163A>G p.Tyr388Cys missense_variant 13/18

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PRKG1ENST00000373980.11 linkuse as main transcriptc.1466A>G p.Tyr489Cys missense_variant 13/181 NM_006258.4 Q13976-2
PRKG1-AS1ENST00000452247.7 linkuse as main transcriptn.461+13064T>C intron_variant, non_coding_transcript_variant 5

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000399
AC:
1
AN:
250544
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135378
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000885
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461214
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
726946
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Aortic aneurysm, familial thoracic 8 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 21, 2021This variant has not been reported in the literature in individuals affected with PRKG1-related conditions. This variant is present in population databases (rs149710600, gnomAD 0.0009%). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 489 of the PRKG1 protein (p.Tyr489Cys). ClinVar contains an entry for this variant (Variation ID: 407089). 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. 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 disruptive. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.52
BayesDel_addAF
Pathogenic
0.41
D
BayesDel_noAF
Pathogenic
0.35
CADD
Pathogenic
32
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.43
T;T;.;.
Eigen
Pathogenic
0.88
Eigen_PC
Pathogenic
0.84
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.99
.;D;.;D
M_CAP
Uncertain
0.17
D
MetaRNN
Pathogenic
0.97
D;D;D;D
MetaSVM
Uncertain
0.41
D
MutationAssessor
Pathogenic
3.1
M;M;.;.
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Pathogenic
0.91
D
PROVEAN
Pathogenic
-8.4
D;.;.;D
REVEL
Pathogenic
0.87
Sift
Uncertain
0.0010
D;.;.;D
Sift4G
Pathogenic
0.0010
.;D;.;D
Polyphen
1.0
D;D;D;D
Vest4
0.92, 0.90
MutPred
0.88
Gain of catalytic residue at L475 (P = 0.1056);Gain of catalytic residue at L475 (P = 0.1056);.;.;
MVP
0.79
MPC
1.8
ClinPred
1.0
D
GERP RS
5.5
Varity_R
0.83
gMVP
0.92

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
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: rs149710600; hg19: chr10-54040611; API