chr10-52280910-C-T

Variant names:

• chr10-52280910-C-T
• rs139646798
• NM_006258.4:c.1525C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. 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. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. H509H) has been classified 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
• Publications: 11 publications found

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

Our verdict: Benign. The variant received -20 ACMG points.

• 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 Benign/Likely_benign. ClinVar VariationId is 414273.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAdExome4 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 GnomAdExome4. There are 560 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 211 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006258.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKG1	NM_006258.4	MANE Select	c.1525C>T	p.His509Tyr	missense	Exon 13 of 18	NP_006249.1
	PRKG1	NM_001098512.3		c.1480C>T	p.His494Tyr	missense	Exon 13 of 18	NP_001091982.1
	PRKG1	NM_001374781.1		c.316C>T	p.His106Tyr	missense	Exon 9 of 14	NP_001361710.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKG1	ENST00000373980.11	TSL:1 MANE Select	c.1525C>T	p.His509Tyr	missense	Exon 13 of 18	ENSP00000363092.5
	PRKG1-AS1	ENST00000426785.2	TSL:1	n.169+13005G>A		intron	N/A
	PRKG1	ENST00000401604.8	TSL:5	c.1480C>T	p.His494Tyr	missense	Exon 13 of 18	ENSP00000384200.4

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

GnomAD2 exomes AF: 0.00195 AC: 489 AN: 250566 AF XY: 0.00168

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 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

African (AFR) AF: 0.000329 AC: 11 AN: 33446

American (AMR) AF: 0.00559 AC: 250 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26108

East Asian (EAS) AF: 0.0170 AC: 676 AN: 39664

South Asian (SAS) AF: 0.000557 AC: 48 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5764

European-Non Finnish (NFE) AF: 0.000124 AC: 138 AN: 1111580

Other (OTH) AF: 0.000994 AC: 60 AN: 60368

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

African (AFR) AF: 0.000578 AC: 24 AN: 41510

American (AMR) AF: 0.00493 AC: 75 AN: 15216

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.0174 AC: 90 AN: 5170

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10584

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 67980

Other (OTH) AF: 0.00331 AC: 7 AN: 2112

Alfa AF: 0.000806 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

Jul 21, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 26, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 27, 2021

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Familial thoracic aortic aneurysm and aortic dissection Benign:1

May 19, 2016

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 v4.9

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
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.93	D
MetaRNN	Benign	0.0096	T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	0.73	N
PhyloP100		4.0
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.15
Sift	Uncertain	0.015	D
Sift4G	Uncertain	0.017	D
Polyphen		0.72	P
Vest4		0.68
MVP		0.47
MPC		0.93
ClinPred		0.0077	T
GERP RS		5.5
Varity_R		0.47
gMVP		0.78
Mutation Taster		=77/23	polymorphism

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

Other links and lift over

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