rs1903974

Variant names:

• chr10-52119317-G-A
• rs1903974
• NM_006258.4:c.936-14523G>A

Variant summary

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

The NM_006258.4(PRKG1):​c.936-14523G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.154 in 152,124 control chromosomes in the GnomAD database, including 2,684 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 0.15 (2684 hom., cov: 32)
• Consequence: PRKG1 NM_006258.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.252
• 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=-0.84).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.307 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.936-14523G>A		intron	N/A	NP_006249.1
	PRKG1	NM_001098512.3		c.891-14523G>A		intron	N/A	NP_001091982.1
	PRKG1	NM_001374781.1		c.-274-14523G>A		intron	N/A	NP_001361710.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKG1	ENST00000373980.11	TSL:1 MANE Select	c.936-14523G>A		intron	N/A	ENSP00000363092.5
	PRKG1	ENST00000401604.8	TSL:5	c.891-14523G>A		intron	N/A	ENSP00000384200.4
	PRKG1	ENST00000373975.3	TSL:2	n.295-14523G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.154 AC: 23439 AN: 152006 Hom.: 2675 Cov.: 32

Gnomad AFR AF: 0.311

Gnomad AMI AF: 0.0429

Gnomad AMR AF: 0.129

Gnomad ASJ AF: 0.120

Gnomad EAS AF: 0.308

Gnomad SAS AF: 0.0951

Gnomad FIN AF: 0.0844

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.0709

Gnomad OTH AF: 0.156

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

GnomAD4 genome AF: 0.154 AC: 23465 AN: 152124 Hom.: 2684 Cov.: 32 AF XY: 0.155 AC XY: 11559 AN XY: 74366

African (AFR) AF: 0.311 AC: 12916 AN: 41490

American (AMR) AF: 0.128 AC: 1963 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.120 AC: 415 AN: 3470

East Asian (EAS) AF: 0.308 AC: 1596 AN: 5180

South Asian (SAS) AF: 0.0948 AC: 457 AN: 4822

European-Finnish (FIN) AF: 0.0844 AC: 895 AN: 10598

Middle Eastern (MID) AF: 0.126 AC: 37 AN: 294

European-Non Finnish (NFE) AF: 0.0709 AC: 4816 AN: 67962

Other (OTH) AF: 0.157 AC: 331 AN: 2114

Alfa AF: 0.0868 Hom.: 523

Bravo AF: 0.166

Asia WGS AF: 0.173 AC: 600 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	6.5
DANN	Benign	0.77
PhyloP100		0.25
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: rs1903974; hg19: chr10-53879077;