rs11000137

Variant names:

• chr10-51922034-G-T
• rs11000137
• NM_006258.4:c.762+14464G>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.762+14464G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.162 in 151,624 control chromosomes in the GnomAD database, including 2,799 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 (2799 hom., cov: 31)
• Consequence: PRKG1 NM_006258.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.403
• Publications: 7 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=-0.81).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.483 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKG1	NM_006258.4	c.762+14464G>T		intron_variant	Intron 5 of 17	ENST00000373980.11	NP_006249.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRKG1	ENST00000373980.11	c.762+14464G>T		intron_variant	Intron 5 of 17	1	NM_006258.4	ENSP00000363092.5
PRKG1	ENST00000401604.8	c.717+14464G>T		intron_variant	Intron 5 of 17	5		ENSP00000384200.4
PRKG1	ENST00000645324.1	c.762+14464G>T		intron_variant	Intron 5 of 7			ENSP00000494124.1
PRKG1	ENST00000373976.9	c.762+14464G>T		intron_variant	Intron 5 of 6	3		ENSP00000363087.4

Frequencies

GnomAD3 genomes AF: 0.162 AC: 24601 AN: 151508 Hom.: 2801 Cov.: 31

Gnomad AFR AF: 0.0491

Gnomad AMI AF: 0.0824

Gnomad AMR AF: 0.197

Gnomad ASJ AF: 0.258

Gnomad EAS AF: 0.499

Gnomad SAS AF: 0.380

Gnomad FIN AF: 0.185

Gnomad MID AF: 0.149

Gnomad NFE AF: 0.175

Gnomad OTH AF: 0.182

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

GnomAD4 genome AF: 0.162 AC: 24597 AN: 151624 Hom.: 2799 Cov.: 31 AF XY: 0.171 AC XY: 12630 AN XY: 74064

African (AFR) AF: 0.0491 AC: 2037 AN: 41452

American (AMR) AF: 0.197 AC: 3003 AN: 15222

Ashkenazi Jewish (ASJ) AF: 0.258 AC: 894 AN: 3466

East Asian (EAS) AF: 0.499 AC: 2557 AN: 5120

South Asian (SAS) AF: 0.379 AC: 1822 AN: 4810

European-Finnish (FIN) AF: 0.185 AC: 1938 AN: 10490

Middle Eastern (MID) AF: 0.143 AC: 42 AN: 294

European-Non Finnish (NFE) AF: 0.175 AC: 11851 AN: 67762

Other (OTH) AF: 0.180 AC: 378 AN: 2098

Alfa AF: 0.178 Hom.: 987

Bravo AF: 0.154

Asia WGS AF: 0.376 AC: 1297 AN: 3456

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	5.1
DANN	Benign	0.77
PhyloP100		-0.40
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: rs11000137; hg19: chr10-53681794;