rs1952138

Variant names:

• chr10-51502873-C-T
• rs1952138
• NM_006258.4:c.592+35037C>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+35037C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.157 in 152,116 control chromosomes in the GnomAD database, including 2,254 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 (2254 hom., cov: 32)
• Consequence: PRKG1 NM_006258.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.157
• 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=-0.82).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.214 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.592+35037C>T		intron	N/A	NP_006249.1
	PRKG1	NM_001098512.3		c.547+35037C>T		intron	N/A	NP_001091982.1
	PRKG1	NM_001374782.1		c.592+35037C>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.592+35037C>T		intron	N/A	ENSP00000363092.5
	PRKG1	ENST00000401604.8	TSL:5	c.547+35037C>T		intron	N/A	ENSP00000384200.4
	PRKG1	ENST00000645324.1		c.592+35037C>T		intron	N/A	ENSP00000494124.1

Frequencies

GnomAD3 genomes AF: 0.157 AC: 23929 AN: 151998 Hom.: 2255 Cov.: 32

Gnomad AFR AF: 0.0747

Gnomad AMI AF: 0.196

Gnomad AMR AF: 0.132

Gnomad ASJ AF: 0.187

Gnomad EAS AF: 0.0506

Gnomad SAS AF: 0.0873

Gnomad FIN AF: 0.204

Gnomad MID AF: 0.196

Gnomad NFE AF: 0.217

Gnomad OTH AF: 0.151

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

GnomAD4 genome AF: 0.157 AC: 23930 AN: 152116 Hom.: 2254 Cov.: 32 AF XY: 0.158 AC XY: 11774 AN XY: 74358

African (AFR) AF: 0.0746 AC: 3100 AN: 41532

American (AMR) AF: 0.132 AC: 2009 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.187 AC: 650 AN: 3470

East Asian (EAS) AF: 0.0501 AC: 259 AN: 5166

South Asian (SAS) AF: 0.0873 AC: 422 AN: 4832

European-Finnish (FIN) AF: 0.204 AC: 2160 AN: 10576

Middle Eastern (MID) AF: 0.201 AC: 59 AN: 294

European-Non Finnish (NFE) AF: 0.217 AC: 14776 AN: 67972

Other (OTH) AF: 0.150 AC: 317 AN: 2112

Alfa AF: 0.168 Hom.: 1890

Bravo AF: 0.148

Asia WGS AF: 0.0700 AC: 243 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.5
DANN	Benign	0.42
PhyloP100		-0.16
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: rs1952138; hg19: chr10-53262633;