10-51801138-C-T

Variant names:

• chr10-51801138-C-T
• rs17629494
• NM_006258.4:c.593-3447C>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.593-3447C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.08 in 152,064 control chromosomes in the GnomAD database, including 535 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 0.080 (535 hom., cov: 32)
• Consequence: PRKG1 NM_006258.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.407
• Publications: 2 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 (NFE) allele frequency at 95% confidence interval = 0.09 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.593-3447C>T		intron	N/A	NP_006249.1
	PRKG1	NM_001098512.3		c.548-3447C>T		intron	N/A	NP_001091982.1
	PRKG1	NM_001374782.1		c.593-3447C>T		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.593-3447C>T		intron	N/A	ENSP00000363092.5
	PRKG1	ENST00000401604.8	TSL:5	c.548-3447C>T		intron	N/A	ENSP00000384200.4
	PRKG1	ENST00000645324.1		c.593-3447C>T		intron	N/A	ENSP00000494124.1

Frequencies

GnomAD3 genomes AF: 0.0801 AC: 12170 AN: 151946 Hom.: 538 Cov.: 32

Gnomad AFR AF: 0.0643

Gnomad AMI AF: 0.0945

Gnomad AMR AF: 0.0526

Gnomad ASJ AF: 0.107

Gnomad EAS AF: 0.0802

Gnomad SAS AF: 0.0800

Gnomad FIN AF: 0.0973

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0919

Gnomad OTH AF: 0.0727

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

GnomAD4 genome AF: 0.0800 AC: 12164 AN: 152064 Hom.: 535 Cov.: 32 AF XY: 0.0788 AC XY: 5856 AN XY: 74330

African (AFR) AF: 0.0642 AC: 2664 AN: 41498

American (AMR) AF: 0.0525 AC: 800 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.107 AC: 371 AN: 3470

East Asian (EAS) AF: 0.0804 AC: 415 AN: 5160

South Asian (SAS) AF: 0.0792 AC: 381 AN: 4810

European-Finnish (FIN) AF: 0.0973 AC: 1031 AN: 10592

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.0919 AC: 6244 AN: 67972

Other (OTH) AF: 0.0705 AC: 149 AN: 2114

Alfa AF: 0.0884 Hom.: 321

Bravo AF: 0.0760

Asia WGS AF: 0.0610 AC: 213 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	5.0
DANN	Benign	0.68
PhyloP100		-0.41
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: rs17629494; hg19: chr10-53560898;