rs139646798

Positions:

• chr10-52280910-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006258.4(PRKG1):​c.1525C>T​(p.His509Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000866 in 1,613,346 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0014 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00081 (13 hom.)
• Consequence: PRKG1 NM_006258.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 4.05

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-AS1 (HGNC:45029): (PRKG1 antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -19 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 3.8719 (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=0.009557843).
• BP6: Variant 10-52280910-C-T is Benign according to our data. Variant chr10-52280910-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 414273.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-52280910-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.000812 (1186/1461272) while in subpopulation EAS AF= 0.017 (676/39664). AF 95% confidence interval is 0.016. There are 13 homozygotes in gnomad4_exome. There are 560 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 211 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRKG1	NM_006258.4	c.1525C>T	p.His509Tyr	missense_variant	13/18	ENST00000373980.11	NP_006249.1
PRKG1	NM_001098512.3	c.1480C>T	p.His494Tyr	missense_variant	13/18		NP_001091982.1
PRKG1	NM_001374781.1	c.316C>T	p.His106Tyr	missense_variant	9/14		NP_001361710.1
PRKG1	XM_017016413.2	c.1222C>T	p.His408Tyr	missense_variant	13/18		XP_016871902.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRKG1	ENST00000373980.11	c.1525C>T	p.His509Tyr	missense_variant	13/18	1	NM_006258.4	ENSP00000363092
PRKG1-AS1	ENST00000452247.7	n.461+13005G>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.00139 AC: 211 AN: 151956 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000580

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00494

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0174

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00195 AC: 489 AN: 250566 Hom.: 3 AF XY: 0.00168 AC XY: 228 AN XY: 135402

Gnomad AFR exome AF: 0.000616

Gnomad AMR exome AF: 0.00542

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0131

Gnomad SAS exome AF: 0.000490

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000212

Gnomad OTH exome AF: 0.00213

GnomAD4 exome AF: 0.000812 AC: 1186 AN: 1461272 Hom.: 13 Cov.: 31 AF XY: 0.000770 AC XY: 560 AN XY: 726904

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.00559

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0170

Gnomad4 SAS exome AF: 0.000557

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000124

Gnomad4 OTH exome AF: 0.000994

GnomAD4 genome AF: 0.00139 AC: 211 AN: 152074 Hom.: 1 Cov.: 32 AF XY: 0.00153 AC XY: 114 AN XY: 74318

Gnomad4 AFR AF: 0.000578

Gnomad4 AMR AF: 0.00493

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0174

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.000801 Hom.: 0

Bravo AF: 0.00166

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00176 AC: 214

Asia WGS AF: 0.00606 AC: 21 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely 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	Jun 26, 2017	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. -

Aortic aneurysm, familial thoracic 8 Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 27, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 27, 2024	- -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 19, 2016

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T;T;.;.
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.93	.;D;.;D
MetaRNN	Benign	0.0096	T;T;T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	0.73	N;N;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-1.5	N;.;.;N
REVEL	Benign	0.15
Sift	Uncertain	0.015	D;.;.;D
Sift4G	Uncertain	0.017	.;D;.;D
Polyphen		0.72	P;P;B;B
Vest4		0.68, 0.70
MVP		0.47
MPC		0.93
ClinPred		0.0077	T
GERP RS		5.5
Varity_R		0.47
gMVP		0.78

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: rs139646798; hg19: chr10-54040670; COSMIC: COSV64771938;