10-50991417-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2 BP4_Strong BP6_Very_Strong BS2

The NM_001098512.3(PRKG1):c.39G>A(p.Met13Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000896 in 1,572,492 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00059 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00093 (0 hom.)
• Consequence: PRKG1 NM_001098512.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 5.04

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 -15 ACMG points.

• PP2: Missense variant where missense usually causes diseases, PRKG1
• BP4: Computational evidence support a benign effect (MetaRNN=0.015071899).
• BP6: Variant 10-50991417-G-A is Benign according to our data. Variant chr10-50991417-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 180475.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-50991417-G-A is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 90 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRKG1	NM_001098512.3	c.39G>A	p.Met13Ile	missense_variant	1/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKG1	ENST00000401604.8	c.39G>A	p.Met13Ile	missense_variant	1/18	5		P1

Frequencies

GnomAD3 genomes AF: 0.000592 AC: 90 AN: 152118 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00104

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000818 AC: 153 AN: 187022 Hom.: 0 AF XY: 0.000855 AC XY: 86 AN XY: 100592

Gnomad AFR exome AF: 0.000108

Gnomad AMR exome AF: 0.000112

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000985

Gnomad FIN exome AF: 0.000853

Gnomad NFE exome AF: 0.00128

Gnomad OTH exome AF: 0.00103

GnomAD4 exome AF: 0.000929 AC: 1319 AN: 1420260 Hom.: 0 Cov.: 34 AF XY: 0.000932 AC XY: 655 AN XY: 703068

Gnomad4 AFR exome AF: 0.000127

Gnomad4 AMR exome AF: 0.000158

Gnomad4 ASJ exome AF: 0.0000793

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00136

Gnomad4 FIN exome AF: 0.000741

Gnomad4 NFE exome AF: 0.00102

Gnomad4 OTH exome AF: 0.000712

GnomAD4 genome AF: 0.000591 AC: 90 AN: 152232 Hom.: 0 Cov.: 31 AF XY: 0.000605 AC XY: 45 AN XY: 74438

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000828

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.00104

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000772 Hom.: 0

Bravo AF: 0.000563

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000264 AC: 1

ESP6500EA AF: 0.000974 AC: 8

ExAC AF: 0.000983 AC: 118

ClinVar

Significance: Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Benign:2

Likely benign, no assertion criteria provided	clinical testing	Blueprint Genetics	Sep 16, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 13, 2024	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. -

PRKG1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 02, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Aortic aneurysm, familial thoracic 8 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Apr 19, 2021

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2023

PRKG1: BP4, BS1 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.21
Cadd	Uncertain	24
Dann	Uncertain	0.98
DEOGEN2	Benign	0.27	T;T
Eigen	Benign	-0.19
Eigen_PC	Benign	0.028
FATHMM_MKL	Uncertain	0.86	D
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.015	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.34	N;N
MutationTaster	Benign	1.0	D;N
PROVEAN	Benign	-0.77	N;.
REVEL	Benign	0.16
Sift	Benign	0.20	T;.
Polyphen		0.0	B;B
Vest4		0.20
MutPred		0.25		Loss of helix (P = 0.0444);Loss of helix (P = 0.0444);
MVP		0.54
ClinPred		0.056	T
GERP RS		4.8
Varity_R		0.43

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: rs202017913; hg19: chr10-52751177;