rs34997494

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_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 (★★). Synonymous variant affecting the same amino acid position (i.e. N282N) has been classified 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:8

Conservation

PhyloP100: 6.97

Publications

17 publications found

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 Gene-Disease associations (from GenCC):

aortic aneurysm, familial thoracic 8
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
familial thoracic aortic aneurysm and aortic dissection
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet

PRKG1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

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 Benign/Likely_benign. ClinVar VariationId is 381196.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
PRKG1	NM_006258.4 link	c.845A>G	p.Asn282Ser	missense_variant	Exon 7 of 18	ENST00000373980.11	NP_006249.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRKG1	ENST00000373980.11 link	c.845A>G	p.Asn282Ser	missense_variant	Exon 7 of 18	1	NM_006258.4	ENSP00000363092.5

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

GnomAD2 exomes

AF:

0.0428

AC:

9722

AN:

227176

AF XY:

0.0446

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 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

African (AFR)

AF:

0.0168

AC:

530

AN:

31574

American (AMR)

AF:

0.0263

AC:

969

AN:

36806

Ashkenazi Jewish (ASJ)

AF:

0.0445

AC:

1093

AN:

24560

East Asian (EAS)

AF:

0.0567

AC:

2227

AN:

39284

South Asian (SAS)

AF:

0.0404

AC:

3253

AN:

80502

European-Finnish (FIN)

AF:

0.0348

AC:

1838

AN:

52888

Middle Eastern (MID)

AF:

0.0401

AC:

225

AN:

5608

European-Non Finnish (NFE)

AF:

0.0528

AC:

57791

AN:

1095186

Other (OTH)

AF:

0.0468

AC:

2750

AN:

58812

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

2730

5461

8191

10922

13652

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2148

4296

6444

8592

10740

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0389

AC:

5922

AN:

152284

Hom.:

120

Cov.:

AF XY:

0.0397

AC XY:

2957

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.0168

AC:

698

AN:

41558

American (AMR)

AF:

0.0398

AC:

609

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0409

AC:

142

AN:

3472

East Asian (EAS)

AF:

0.0466

AC:

241

AN:

5174

South Asian (SAS)

AF:

0.0429

AC:

207

AN:

4828

European-Finnish (FIN)

AF:

0.0418

AC:

444

AN:

10616

Middle Eastern (MID)

AF:

0.0408

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0504

AC:

3429

AN:

68016

Other (OTH)

AF:

0.0515

AC:

109

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

299

597

896

1194

1493

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

198

264

330

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0483

Hom.:

639

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:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Apr 10, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 28, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Familial thoracic aortic aneurysm and aortic dissection

Benign:2

Nov 18, 2022

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 30, 2015

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Nov 20, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

(source)

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;.;.;.;.

PhyloP100

7.0

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

Mutation Taster

=267/33

polymorphism (auto)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over