rs6480499

Variant names:

• chr10-51834219-C-T
• rs6480499
• NM_006258.4:c.698+29529C>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.698+29529C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.402 in 151,962 control chromosomes in the GnomAD database, including 14,155 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 0.40 (14155 hom., cov: 31)
• Consequence: PRKG1 NM_006258.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.130
• Publications: 5 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=-0.97).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.514 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKG1	NM_006258.4	c.698+29529C>T		intron_variant	Intron 4 of 17	ENST00000373980.11	NP_006249.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRKG1	ENST00000373980.11	c.698+29529C>T		intron_variant	Intron 4 of 17	1	NM_006258.4	ENSP00000363092.5

Frequencies

GnomAD3 genomes AF: 0.402 AC: 61090 AN: 151844 Hom.: 14160 Cov.: 31

Gnomad AFR AF: 0.169

Gnomad AMI AF: 0.558

Gnomad AMR AF: 0.395

Gnomad ASJ AF: 0.522

Gnomad EAS AF: 0.459

Gnomad SAS AF: 0.436

Gnomad FIN AF: 0.473

Gnomad MID AF: 0.535

Gnomad NFE AF: 0.519

Gnomad OTH AF: 0.432

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

GnomAD4 genome AF: 0.402 AC: 61092 AN: 151962 Hom.: 14155 Cov.: 31 AF XY: 0.402 AC XY: 29874 AN XY: 74264

African (AFR) AF: 0.168 AC: 6982 AN: 41446

American (AMR) AF: 0.395 AC: 6019 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.522 AC: 1811 AN: 3468

East Asian (EAS) AF: 0.458 AC: 2371 AN: 5172

South Asian (SAS) AF: 0.437 AC: 2107 AN: 4820

European-Finnish (FIN) AF: 0.473 AC: 4983 AN: 10528

Middle Eastern (MID) AF: 0.531 AC: 156 AN: 294

European-Non Finnish (NFE) AF: 0.519 AC: 35254 AN: 67964

Other (OTH) AF: 0.427 AC: 902 AN: 2114

Alfa AF: 0.483 Hom.: 78668

Bravo AF: 0.386

Asia WGS AF: 0.419 AC: 1452 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	2.4
DANN	Benign	0.59
PhyloP100		-0.13
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: rs6480499; hg19: chr10-53593979;