10-51588288-C-T

Variant names:

• chr10-51588288-C-T
• rs1922127
• NM_006258.4:c.592+120452C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006258.4(PRKG1):​c.592+120452C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.158 in 151,958 control chromosomes in the GnomAD database, including 1,983 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.16 (1983 hom., cov: 33)
• Consequence: PRKG1 NM_006258.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.700
• Publications: 3 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 Gene-Disease associations (from GenCC):

• aortic aneurysm, familial thoracic 8

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.196 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKG1	NM_006258.4	c.592+120452C>T		intron_variant	Intron 3 of 17	ENST00000373980.11	NP_006249.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRKG1	ENST00000373980.11	c.592+120452C>T		intron_variant	Intron 3 of 17	1	NM_006258.4	ENSP00000363092.5

Frequencies

GnomAD3 genomes AF: 0.158 AC: 23962 AN: 151840 Hom.: 1984 Cov.: 33

Gnomad AFR AF: 0.200

Gnomad AMI AF: 0.173

Gnomad AMR AF: 0.140

Gnomad ASJ AF: 0.174

Gnomad EAS AF: 0.0181

Gnomad SAS AF: 0.175

Gnomad FIN AF: 0.125

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.151

Gnomad OTH AF: 0.144

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.158 AC: 23983 AN: 151958 Hom.: 1983 Cov.: 33 AF XY: 0.156 AC XY: 11571 AN XY: 74276

African (AFR) AF: 0.199 AC: 8263 AN: 41434

American (AMR) AF: 0.140 AC: 2136 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.174 AC: 605 AN: 3470

East Asian (EAS) AF: 0.0178 AC: 92 AN: 5170

South Asian (SAS) AF: 0.174 AC: 838 AN: 4814

European-Finnish (FIN) AF: 0.125 AC: 1314 AN: 10540

Middle Eastern (MID) AF: 0.122 AC: 36 AN: 294

European-Non Finnish (NFE) AF: 0.151 AC: 10235 AN: 67962

Other (OTH) AF: 0.145 AC: 307 AN: 2114

Alfa AF: 0.146 Hom.: 3069

Bravo AF: 0.157

Asia WGS AF: 0.134 AC: 463 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.5
DANN	Benign	0.63
PhyloP100		-0.70
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1922127; hg19: chr10-53348048;