rs56047641

Positions:

chr10-52161895-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The ENST00000373980.11(PRKG1):c.1008T>C(p.Phe336=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.012 in 1,612,610 control chromosomes in the GnomAD database, including 1,135 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.049 ( 515 hom., cov: 33)

Exomes 𝑓: 0.0082 ( 620 hom. )

Consequence

PRKG1
ENST00000373980.11 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 2.10

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.54).

BP6

Variant 10-52161895-T-C is Benign according to our data. Variant chr10-52161895-T-C is described in ClinVar as [Benign]. Clinvar id is 263888.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-52161895-T-C is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=2.1 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.156 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.1008T>C	p.Phe336=	synonymous_variant	9/18	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.1008T>C	p.Phe336=	synonymous_variant	9/18	1	NM_006258.4	ENSP00000363092		Q13976-2

Frequencies

GnomAD3 genomes

AF:

0.0489

AC:

7434

AN:

152036

Hom.:

514

Cov.:

show subpopulations

Gnomad AFR

AF:

0.160

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0158

Gnomad ASJ

AF:

0.000866

Gnomad EAS

AF:

0.0594

Gnomad SAS

AF:

0.0273

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000780

Gnomad OTH

AF:

0.0406

GnomAD3 exomes

AF:

0.0202

AC:

5070

AN:

250492

Hom.:

281

AF XY:

0.0178

AC XY:

2406

AN XY:

135396

show subpopulations

Gnomad AFR exome

AF:

0.166

Gnomad AMR exome

AF:

0.00774

Gnomad ASJ exome

AF:

0.00119

Gnomad EAS exome

AF:

0.0588

Gnomad SAS exome

AF:

0.0295

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000486

Gnomad OTH exome

AF:

0.0116

GnomAD4 exome

AF:

0.00820

AC:

11973

AN:

1460456

Hom.:

620

Cov.:

AF XY:

0.00820

AC XY:

5955

AN XY:

726532

show subpopulations

Gnomad4 AFR exome

AF:

0.165

Gnomad4 AMR exome

AF:

0.00906

Gnomad4 ASJ exome

AF:

0.00119

Gnomad4 EAS exome

AF:

0.0530

Gnomad4 SAS exome

AF:

0.0287

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.000378

Gnomad4 OTH exome

AF:

0.0164

GnomAD4 genome

AF:

0.0490

AC:

7448

AN:

152154

Hom.:

515

Cov.:

AF XY:

0.0485

AC XY:

3607

AN XY:

74402

show subpopulations

Gnomad4 AFR

AF:

0.160

Gnomad4 AMR

AF:

0.0158

Gnomad4 ASJ

AF:

0.000866

Gnomad4 EAS

AF:

0.0588

Gnomad4 SAS

AF:

0.0275

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000780

Gnomad4 OTH

AF:

0.0402

Alfa

AF:

0.0193

Hom.:

122

Bravo

AF:

0.0563

Asia WGS

AF:

0.0570

AC:

197

AN:

3476

EpiCase

AF:

0.000872

EpiControl

AF:

0.000652

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 20, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 09, 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	Dec 01, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 03, 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. -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Aortic aneurysm, familial thoracic 8

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.54

CADD

Benign

9.0

DANN

Benign

0.75

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