NM_006258.4:c.762+40419T>A

Variant names:

• chr10-51947989-T-A
• rs7092969
• NM_006258.4:c.762+40419T>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.762+40419T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.78 in 152,158 control chromosomes in the GnomAD database, including 46,898 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 0.78 (46898 hom., cov: 32)
• Consequence: PRKG1 NM_006258.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.109
• Publications: 1 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 = 0.89 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKG1	NM_006258.4	c.762+40419T>A		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+40419T>A		intron_variant	Intron 5 of 17	1	NM_006258.4	ENSP00000363092.5
PRKG1	ENST00000401604.8	c.717+40419T>A		intron_variant	Intron 5 of 17	5		ENSP00000384200.4
PRKG1	ENST00000645324.1	c.762+40419T>A		intron_variant	Intron 5 of 7			ENSP00000494124.1
PRKG1	ENST00000373976.9	c.762+40419T>A		intron_variant	Intron 5 of 6	3		ENSP00000363087.4

Frequencies

GnomAD3 genomes AF: 0.780 AC: 118652 AN: 152040 Hom.: 46852 Cov.: 32

Gnomad AFR AF: 0.898

Gnomad AMI AF: 0.779

Gnomad AMR AF: 0.711

Gnomad ASJ AF: 0.718

Gnomad EAS AF: 0.740

Gnomad SAS AF: 0.761

Gnomad FIN AF: 0.671

Gnomad MID AF: 0.741

Gnomad NFE AF: 0.749

Gnomad OTH AF: 0.790

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

GnomAD4 genome AF: 0.780 AC: 118755 AN: 152158 Hom.: 46898 Cov.: 32 AF XY: 0.776 AC XY: 57704 AN XY: 74382

African (AFR) AF: 0.898 AC: 37301 AN: 41544

American (AMR) AF: 0.711 AC: 10862 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.718 AC: 2493 AN: 3470

East Asian (EAS) AF: 0.740 AC: 3825 AN: 5170

South Asian (SAS) AF: 0.760 AC: 3669 AN: 4826

European-Finnish (FIN) AF: 0.671 AC: 7086 AN: 10560

Middle Eastern (MID) AF: 0.735 AC: 216 AN: 294

European-Non Finnish (NFE) AF: 0.749 AC: 50920 AN: 67994

Other (OTH) AF: 0.791 AC: 1673 AN: 2114

Alfa AF: 0.683 Hom.: 1980

Bravo AF: 0.785

Asia WGS AF: 0.779 AC: 2709 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	3.6
DANN	Benign	0.24
PhyloP100		0.11
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: rs7092969; hg19: chr10-53707749;