10-51718953-A-C

Variant names:

• chr10-51718953-A-C
• rs4400745
• NM_006258.4:c.593-85632A>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.593-85632A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.581 in 151,974 control chromosomes in the GnomAD database, including 26,324 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 0.58 (26324 hom., cov: 32)
• Consequence: PRKG1 NM_006258.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.83
• Publications: 4 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=-1.01).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.653 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKG1	NM_006258.4	MANE Select	c.593-85632A>C		intron	N/A	NP_006249.1
	PRKG1	NM_001098512.3		c.548-85632A>C		intron	N/A	NP_001091982.1
	PRKG1	NM_001374782.1		c.593-85632A>C		intron	N/A	NP_001361711.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKG1	ENST00000373980.11	TSL:1 MANE Select	c.593-85632A>C		intron	N/A	ENSP00000363092.5
	PRKG1	ENST00000401604.8	TSL:5	c.548-85632A>C		intron	N/A	ENSP00000384200.4
	PRKG1	ENST00000645324.1		c.593-85632A>C		intron	N/A	ENSP00000494124.1

Frequencies

GnomAD3 genomes AF: 0.581 AC: 88296 AN: 151854 Hom.: 26296 Cov.: 32

Gnomad AFR AF: 0.660

Gnomad AMI AF: 0.513

Gnomad AMR AF: 0.438

Gnomad ASJ AF: 0.661

Gnomad EAS AF: 0.270

Gnomad SAS AF: 0.485

Gnomad FIN AF: 0.579

Gnomad MID AF: 0.652

Gnomad NFE AF: 0.594

Gnomad OTH AF: 0.567

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

GnomAD4 genome AF: 0.581 AC: 88369 AN: 151974 Hom.: 26324 Cov.: 32 AF XY: 0.577 AC XY: 42842 AN XY: 74260

African (AFR) AF: 0.660 AC: 27357 AN: 41468

American (AMR) AF: 0.438 AC: 6682 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.661 AC: 2294 AN: 3470

East Asian (EAS) AF: 0.270 AC: 1390 AN: 5146

South Asian (SAS) AF: 0.486 AC: 2340 AN: 4818

European-Finnish (FIN) AF: 0.579 AC: 6100 AN: 10542

Middle Eastern (MID) AF: 0.663 AC: 195 AN: 294

European-Non Finnish (NFE) AF: 0.594 AC: 40365 AN: 67954

Other (OTH) AF: 0.561 AC: 1181 AN: 2106

Alfa AF: 0.589 Hom.: 101375

Bravo AF: 0.575

Asia WGS AF: 0.422 AC: 1473 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.70
DANN	Benign	0.55
PhyloP100		-1.8
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: rs4400745; hg19: chr10-53478713;