rs34997494

Positions:

chr10-52062541-A-G

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 3P and 20B. PM1PP2BP4_StrongBP6_Very_StrongBA1

The NM_006258.4(PRKG1):c.845A>G(p.Asn282Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0486 in 1,577,504 control chromosomes in the GnomAD database, including 1,976 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.039 ( 120 hom., cov: 32)

Exomes 𝑓: 0.050 ( 1856 hom. )

Consequence

PRKG1
NM_006258.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 6.97

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -17 ACMG points.

PM1

In a binding_site (size 0) in uniprot entity KGP1_HUMAN

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=0.0063574016).

BP6

Variant 10-52062541-A-G is Benign according to our data. Variant chr10-52062541-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 381196.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-52062541-A-G is described in Lovd as [Benign].

BA1

GnomAdExome4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0547 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRKG1	NM_006258.4 linkuse as main transcript	c.845A>G	p.Asn282Ser	missense_variant	7/18	ENST00000373980.11	NP_006249.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRKG1	ENST00000373980.11 linkuse as main transcript	c.845A>G	p.Asn282Ser	missense_variant	7/18	1	NM_006258.4	ENSP00000363092		Q13976-2

Frequencies

GnomAD3 genomes

AF:

0.0389

AC:

5925

AN:

152166

Hom.:

120

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0169

Gnomad AMI

AF:

0.0340

Gnomad AMR

AF:

0.0399

Gnomad ASJ

AF:

0.0409

Gnomad EAS

AF:

0.0467

Gnomad SAS

AF:

0.0422

Gnomad FIN

AF:

0.0418

Gnomad MID

AF:

0.0443

Gnomad NFE

AF:

0.0505

Gnomad OTH

AF:

0.0511

GnomAD3 exomes

AF:

0.0428

AC:

9722

AN:

227176

Hom.:

228

AF XY:

0.0446

AC XY:

5485

AN XY:

123078

show subpopulations

Gnomad AFR exome

AF:

0.0187

Gnomad AMR exome

AF:

0.0237

Gnomad ASJ exome

AF:

0.0440

Gnomad EAS exome

AF:

0.0493

Gnomad SAS exome

AF:

0.0382

Gnomad FIN exome

AF:

0.0377

Gnomad NFE exome

AF:

0.0521

Gnomad OTH exome

AF:

0.0449

GnomAD4 exome

AF:

0.0496

AC:

70676

AN:

1425220

Hom.:

1856

Cov.:

AF XY:

0.0497

AC XY:

35235

AN XY:

709384

show subpopulations

Gnomad4 AFR exome

AF:

0.0168

Gnomad4 AMR exome

AF:

0.0263

Gnomad4 ASJ exome

AF:

0.0445

Gnomad4 EAS exome

AF:

0.0567

Gnomad4 SAS exome

AF:

0.0404

Gnomad4 FIN exome

AF:

0.0348

Gnomad4 NFE exome

AF:

0.0528

Gnomad4 OTH exome

AF:

0.0468

GnomAD4 genome

AF:

0.0389

AC:

5922

AN:

152284

Hom.:

120

Cov.:

AF XY:

0.0397

AC XY:

2957

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.0168

Gnomad4 AMR

AF:

0.0398

Gnomad4 ASJ

AF:

0.0409

Gnomad4 EAS

AF:

0.0466

Gnomad4 SAS

AF:

0.0429

Gnomad4 FIN

AF:

0.0418

Gnomad4 NFE

AF:

0.0504

Gnomad4 OTH

AF:

0.0515

Alfa

AF:

0.0488

Hom.:

316

Bravo

AF:

0.0379

TwinsUK

AF:

0.0515

AC:

191

ALSPAC

AF:

0.0488

AC:

188

ESP6500AA

AF:

0.0170

AC:

ESP6500EA

AF:

0.0480

AC:

413

ExAC

AF:

0.0425

AC:

5163

Asia WGS

AF:

0.0420

AC:

145

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 28, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 10, 2023	- -

Familial thoracic aortic aneurysm and aortic dissection

Benign:2

Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Nov 18, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 30, 2015	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Aortic aneurysm, familial thoracic 8

Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 30, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.19

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.51

D;D;.;.;.;.

Eigen

Benign

-0.20

Eigen_PC

Benign

0.082

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.88

.;D;D;.;D;D

MetaRNN

Benign

0.0064

T;T;T;T;T;T

MetaSVM

Benign

-0.56

MutationAssessor

Benign

-0.38

N;N;.;.;.;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-0.84

N;.;.;.;N;.

REVEL

Uncertain

0.33

Sift

Benign

0.058

T;.;.;.;T;.

Sift4G

Benign

0.19

.;T;.;.;T;.

Polyphen

0.0010

B;B;.;B;B;.

Vest4

0.49, 0.54

MPC

0.50

ClinPred

0.022

GERP RS

5.8

Varity_R

0.26

gMVP

0.52

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over