10-52013039-T-C

Variant names:

• chr10-52013039-T-C
• rs7893146
• NM_006258.4:c.763-41445T>C

Variant summary

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

The NM_006258.4(PRKG1):​c.763-41445T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.744 in 152,088 control chromosomes in the GnomAD database, including 42,429 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 0.74 (42429 hom., cov: 32)
• Consequence: PRKG1 NM_006258.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.620
• 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, Unknown Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen

ENSG00000289527 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.8 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKG1	NM_006258.4	MANE Select	c.763-41445T>C		intron	N/A	NP_006249.1	Q13976-2
	PRKG1	NM_001098512.3		c.718-41445T>C		intron	N/A	NP_001091982.1	Q13976-1
	PRKG1	NM_001374782.1		c.763-41445T>C		intron	N/A	NP_001361711.1	B1ALS0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKG1	ENST00000373980.11	TSL:1 MANE Select	c.763-41445T>C		intron	N/A	ENSP00000363092.5	Q13976-2
	PRKG1	ENST00000401604.8	TSL:5	c.718-41445T>C		intron	N/A	ENSP00000384200.4	Q13976-1
	PRKG1	ENST00000645324.1		c.763-41445T>C		intron	N/A	ENSP00000494124.1	A0A2R8Y507

Frequencies

GnomAD3 genomes AF: 0.744 AC: 113092 AN: 151970 Hom.: 42408 Cov.: 32

Gnomad AFR AF: 0.807

Gnomad AMI AF: 0.747

Gnomad AMR AF: 0.683

Gnomad ASJ AF: 0.709

Gnomad EAS AF: 0.734

Gnomad SAS AF: 0.750

Gnomad FIN AF: 0.653

Gnomad MID AF: 0.756

Gnomad NFE AF: 0.736

Gnomad OTH AF: 0.753

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

GnomAD4 genome AF: 0.744 AC: 113170 AN: 152088 Hom.: 42429 Cov.: 32 AF XY: 0.740 AC XY: 55003 AN XY: 74326

African (AFR) AF: 0.807 AC: 33459 AN: 41468

American (AMR) AF: 0.683 AC: 10432 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.709 AC: 2463 AN: 3472

East Asian (EAS) AF: 0.733 AC: 3788 AN: 5168

South Asian (SAS) AF: 0.749 AC: 3611 AN: 4822

European-Finnish (FIN) AF: 0.653 AC: 6901 AN: 10566

Middle Eastern (MID) AF: 0.748 AC: 220 AN: 294

European-Non Finnish (NFE) AF: 0.736 AC: 50021 AN: 67992

Other (OTH) AF: 0.755 AC: 1594 AN: 2112

Alfa AF: 0.726 Hom.: 17915

Bravo AF: 0.745

Asia WGS AF: 0.760 AC: 2644 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	1.0
DANN	Benign	0.44
PhyloP100		-0.62
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: rs7893146; hg19: chr10-53772799;