chr10-51153260-G-A

Position:

chr10-51153260-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_006258.4(PRKG1):c.408G>A(p.Pro136=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0199 in 1,612,374 control chromosomes in the GnomAD database, including 434 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.017 ( 40 hom., cov: 31)

Exomes 𝑓: 0.020 ( 394 hom. )

Consequence

PRKG1
NM_006258.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -4.08

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=-0.64).

BP6

Variant 10-51153260-G-A is Benign according to our data. Variant chr10-51153260-G-A is described in ClinVar as [Benign]. Clinvar id is 220801.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-51153260-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-4.07 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0173 (2627/152044) while in subpopulation NFE AF= 0.0235 (1599/67920). AF 95% confidence interval is 0.0226. There are 40 homozygotes in gnomad4. There are 1305 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High AC in GnomAd4 at 2627 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRKG1	NM_006258.4 linkuse as main transcript	c.408G>A	p.Pro136=	synonymous_variant	2/18	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.408G>A	p.Pro136=	synonymous_variant	2/18	1	NM_006258.4	ENSP00000363092		Q13976-2

Frequencies

GnomAD3 genomes

AF:

0.0173

AC:

2630

AN:

151926

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00515

Gnomad AMI

AF:

0.0121

Gnomad AMR

AF:

0.0183

Gnomad ASJ

AF:

0.0268

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00871

Gnomad FIN

AF:

0.0318

Gnomad MID

AF:

0.0411

Gnomad NFE

AF:

0.0236

Gnomad OTH

AF:

0.0196

GnomAD3 exomes

AF:

0.0172

AC:

4315

AN:

250736

Hom.:

AF XY:

0.0174

AC XY:

2365

AN XY:

135536

show subpopulations

Gnomad AFR exome

AF:

0.00502

Gnomad AMR exome

AF:

0.00943

Gnomad ASJ exome

AF:

0.0269

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00840

Gnomad FIN exome

AF:

0.0316

Gnomad NFE exome

AF:

0.0227

Gnomad OTH exome

AF:

0.0206

GnomAD4 exome

AF:

0.0202

AC:

29480

AN:

1460330

Hom.:

394

Cov.:

AF XY:

0.0202

AC XY:

14643

AN XY:

726482

show subpopulations

Gnomad4 AFR exome

AF:

0.00468

Gnomad4 AMR exome

AF:

0.0107

Gnomad4 ASJ exome

AF:

0.0279

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00860

Gnomad4 FIN exome

AF:

0.0307

Gnomad4 NFE exome

AF:

0.0219

Gnomad4 OTH exome

AF:

0.0207

GnomAD4 genome

AF:

0.0173

AC:

2627

AN:

152044

Hom.:

Cov.:

AF XY:

0.0176

AC XY:

1305

AN XY:

74332

show subpopulations

Gnomad4 AFR

AF:

0.00516

Gnomad4 AMR

AF:

0.0183

Gnomad4 ASJ

AF:

0.0268

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00830

Gnomad4 FIN

AF:

0.0318

Gnomad4 NFE

AF:

0.0235

Gnomad4 OTH

AF:

0.0190

Alfa

AF:

0.0214

Hom.:

Bravo

AF:

0.0159

Asia WGS

AF:

0.00606

AC:

AN:

3478

EpiCase

AF:

0.0261

EpiControl

AF:

0.0217

ClinVar

Significance: 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 27, 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. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 21, 2023	- -

Familial thoracic aortic aneurysm and aortic dissection

Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Dec 13, 2022	- -

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

BayesDel_noAF

Benign

-0.64

CADD

Benign

1.0

DANN

Benign

0.68

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