rs55754654

chr10-51153278-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS2

The NM_006258.4(PRKG1):c.426C>T(p.Asp142=) variant causes a synonymous change. The variant allele was found at a frequency of 0.00577 in 1,612,176 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0042 (2 hom., cov: 31)
  • Exomes 𝑓: 0.0059 (32 hom.)
• Consequence: PRKG1 NM_006258.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 4.46

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BP6: Variant 10-51153278-C-T is Benign according to our data. Variant chr10-51153278-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 240642.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-51153278-C-T is described in Lovd as [Benign]. Variant chr10-51153278-C-T is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 638 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRKG1	NM_006258.4	c.426C>T	p.Asp142=	synonymous_variant	2/18	ENST00000373980.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKG1	ENST00000373980.11	c.426C>T	p.Asp142=	synonymous_variant	2/18	1	NM_006258.4

Frequencies

GnomAD3 genomes AF: 0.00420 AC: 638 AN: 151908 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.00111

Gnomad AMI AF: 0.0340

Gnomad AMR AF: 0.00230

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.000849

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00726

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00391 AC: 979 AN: 250544 Hom.: 3 AF XY: 0.00388 AC XY: 525 AN XY: 135406

Gnomad AFR exome AF: 0.00205

Gnomad AMR exome AF: 0.00291

Gnomad ASJ exome AF: 0.00268

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00147

Gnomad FIN exome AF: 0.00120

Gnomad NFE exome AF: 0.00623

Gnomad OTH exome AF: 0.00688

GnomAD4 exome AF: 0.00593 AC: 8658 AN: 1460150 Hom.: 32 Cov.: 30 AF XY: 0.00574 AC XY: 4168 AN XY: 726398

Gnomad4 AFR exome AF: 0.00114

Gnomad4 AMR exome AF: 0.00298

Gnomad4 ASJ exome AF: 0.00322

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00138

Gnomad4 FIN exome AF: 0.00146

Gnomad4 NFE exome AF: 0.00705

Gnomad4 OTH exome AF: 0.00609

GnomAD4 genome AF: 0.00420 AC: 638 AN: 152026 Hom.: 2 Cov.: 31 AF XY: 0.00353 AC XY: 262 AN XY: 74300

Gnomad4 AFR AF: 0.00111

Gnomad4 AMR AF: 0.00230

Gnomad4 ASJ AF: 0.00375

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.000849

Gnomad4 NFE AF: 0.00726

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00619 Hom.: 2

Bravo AF: 0.00428

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00705

EpiControl AF: 0.00570

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 21, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 13, 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, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

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 08, 2023	- -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	PRKG1: BP4, BS2 -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 08, 2015

This alteration is classified as likely 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
Cadd	Benign	11
Dann	Benign	0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs55754654; hg19: chr10-52913038;