chr10-50991417-G-A

Position:

chr10-50991417-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2BP4_StrongBP6_Very_StrongBS2

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

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 5.04

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 -15 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PRKG1. . Gene score misZ 2.982 (greater than the threshold 3.09). Trascript score misZ 3.2199 (greater than threshold 3.09). GenCC has associacion of gene with familial thoracic aortic aneurysm and aortic dissection, aortic aneurysm, familial thoracic 8.

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 GnomAd4 at 90 AD gene.

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKG1	ENST00000401604.8 linkuse as main transcript	c.39G>A	p.Met13Ile	missense_variant	1/18	5		P1	Q13976-1

Frequencies

GnomAD3 genomes

AF:

0.000592

AC:

AN:

152118

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.000855

AC XY:

AN XY:

100592

show subpopulations

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.:

Cov.:

AF XY:

0.000932

AC XY:

655

AN XY:

703068

show subpopulations

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:

AN:

152232

Hom.:

Cov.:

AF XY:

0.000605

AC XY:

AN XY:

74438

show subpopulations

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.:

Bravo

AF:

0.000563

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000264

AC:

ESP6500EA

AF:

0.000974

AC:

ExAC

AF:

0.000983

AC:

118

ClinVar

Significance: Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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, no assertion criteria provided

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

BayesDel_noAF

Benign

-0.21

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Benign

0.27

T;T

Eigen

Benign

-0.19

Eigen_PC

Benign

0.028

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.74

.;T

M_CAP

Benign

0.049

MetaRNN

Benign

0.015

T;T

MetaSVM

Benign

-0.99

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;.

Sift4G

Benign

0.23

.;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

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

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