rs55806342

chr10-51153260-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

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 (★★). Synonymous variant affecting the same amino acid position (i.e. P136P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.017 (40 hom., cov: 31)
  • Exomes 𝑓: 0.020 (394 hom.)
• Consequence: PRKG1 NM_006258.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -4.08

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]

ACMG classification

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. This position pass quality control queck.
• BS2: High AC in GnomAd at 2630 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRKG1	NM_006258.4	c.408G>A	p.Pro136=	synonymous_variant	2/18	ENST00000373980.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKG1	ENST00000373980.11	c.408G>A	p.Pro136=	synonymous_variant	2/18	1	NM_006258.4

Frequencies

GnomAD3 genomes AF: 0.0173 AC: 2630 AN: 151926 Hom.: 41 Cov.: 31

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.: 59 AF XY: 0.0174 AC XY: 2365 AN XY: 135536

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.: 30 AF XY: 0.0202 AC XY: 14643 AN XY: 726482

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.: 40 Cov.: 31 AF XY: 0.0176 AC XY: 1305 AN XY: 74332

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.: 17

Bravo AF: 0.0159

Asia WGS AF: 0.00606 AC: 21 AN: 3478

EpiCase AF: 0.0261

EpiControl AF: 0.0217

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

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

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

Other links and lift over

dbSNP: rs55806342; hg19: chr10-52913020;