10-51029595-T-C

Variant names:

• chr10-51029595-T-C
• rs6479874
• NM_001098512.3:c.266+37951T>C

Variant summary

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

The NM_001098512.3(PRKG1):​c.266+37951T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.879 in 152,158 control chromosomes in the GnomAD database, including 58,890 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 0.88 (58890 hom., cov: 32)
• Consequence: PRKG1 NM_001098512.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.00100
• Publications: 9 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=-0.96).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.906 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001098512.3. 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_001098512.3		c.266+37951T>C		intron	N/A	NP_001091982.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKG1	ENST00000401604.8	TSL:5	c.266+37951T>C		intron	N/A	ENSP00000384200.4

Frequencies

GnomAD3 genomes AF: 0.879 AC: 133652 AN: 152040 Hom.: 58843 Cov.: 32

Gnomad AFR AF: 0.913

Gnomad AMI AF: 0.874

Gnomad AMR AF: 0.878

Gnomad ASJ AF: 0.876

Gnomad EAS AF: 0.928

Gnomad SAS AF: 0.823

Gnomad FIN AF: 0.851

Gnomad MID AF: 0.835

Gnomad NFE AF: 0.864

Gnomad OTH AF: 0.877

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

GnomAD4 genome AF: 0.879 AC: 133756 AN: 152158 Hom.: 58890 Cov.: 32 AF XY: 0.877 AC XY: 65248 AN XY: 74378

African (AFR) AF: 0.913 AC: 37912 AN: 41528

American (AMR) AF: 0.878 AC: 13398 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.876 AC: 3040 AN: 3472

East Asian (EAS) AF: 0.928 AC: 4803 AN: 5176

South Asian (SAS) AF: 0.823 AC: 3960 AN: 4812

European-Finnish (FIN) AF: 0.851 AC: 9009 AN: 10592

Middle Eastern (MID) AF: 0.844 AC: 248 AN: 294

European-Non Finnish (NFE) AF: 0.864 AC: 58739 AN: 67996

Other (OTH) AF: 0.877 AC: 1850 AN: 2110

Alfa AF: 0.867 Hom.: 31115

Bravo AF: 0.886

Asia WGS AF: 0.893 AC: 3105 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	3.6
DANN	Benign	0.64
PhyloP100		-0.0010
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: rs6479874; hg19: chr10-52789355;