rs10762540

Variant names:

• chr10-52029907-A-C
• rs10762540
• NM_006258.4:c.763-24577A>C

Variant summary

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

The NM_006258.4(PRKG1):​c.763-24577A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.513 in 151,830 control chromosomes in the GnomAD database, including 20,375 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 0.51 (20375 hom., cov: 31)
• Consequence: PRKG1 NM_006258.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.38
• 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

ENSG00000289527 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.606 is higher than 0.05.

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.763-24577A>C		intron	N/A	NP_006249.1
	PRKG1	NM_001098512.3		c.718-24577A>C		intron	N/A	NP_001091982.1
	PRKG1	NM_001374782.1		c.763-24577A>C		intron	N/A	NP_001361711.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKG1	ENST00000373980.11	TSL:1 MANE Select	c.763-24577A>C		intron	N/A	ENSP00000363092.5
	PRKG1	ENST00000401604.8	TSL:5	c.718-24577A>C		intron	N/A	ENSP00000384200.4
	PRKG1	ENST00000645324.1		c.763-24577A>C		intron	N/A	ENSP00000494124.1

Frequencies

GnomAD3 genomes AF: 0.513 AC: 77831 AN: 151712 Hom.: 20338 Cov.: 31

Gnomad AFR AF: 0.612

Gnomad AMI AF: 0.465

Gnomad AMR AF: 0.550

Gnomad ASJ AF: 0.449

Gnomad EAS AF: 0.529

Gnomad SAS AF: 0.404

Gnomad FIN AF: 0.502

Gnomad MID AF: 0.468

Gnomad NFE AF: 0.457

Gnomad OTH AF: 0.489

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

GnomAD4 genome AF: 0.513 AC: 77928 AN: 151830 Hom.: 20375 Cov.: 31 AF XY: 0.514 AC XY: 38128 AN XY: 74200

African (AFR) AF: 0.613 AC: 25347 AN: 41366

American (AMR) AF: 0.551 AC: 8404 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.449 AC: 1557 AN: 3466

East Asian (EAS) AF: 0.528 AC: 2717 AN: 5148

South Asian (SAS) AF: 0.405 AC: 1945 AN: 4804

European-Finnish (FIN) AF: 0.502 AC: 5288 AN: 10544

Middle Eastern (MID) AF: 0.459 AC: 135 AN: 294

European-Non Finnish (NFE) AF: 0.458 AC: 31076 AN: 67924

Other (OTH) AF: 0.489 AC: 1035 AN: 2116

Alfa AF: 0.512 Hom.: 3437

Bravo AF: 0.527

Asia WGS AF: 0.488 AC: 1695 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.37
DANN	Benign	0.60
PhyloP100		-1.4
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: rs10762540; hg19: chr10-53789667;