10-50991778-C-A

Variant names:

• chr10-50991778-C-A
• rs183264171
• NM_001098512.3:c.266+134C>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001098512.3(PRKG1):​c.266+134C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0015 in 582,828 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0046 (3 hom., cov: 31)
  • Exomes 𝑓: 0.00041 (2 hom.)
• Consequence: PRKG1 NM_001098512.3 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.630
• Publications: 0 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

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 10-50991778-C-A is Benign according to our data. Variant chr10-50991778-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 1218770.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00462 (699/151252) while in subpopulation AFR AF = 0.0161 (667/41390). AF 95% confidence interval is 0.0151. There are 3 homozygotes in GnomAd4. There are 314 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 699 AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKG1	NM_001098512.3		c.266+134C>A		intron	N/A	NP_001091982.1	Q13976-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKG1	ENST00000401604.8	TSL:5	c.266+134C>A		intron	N/A	ENSP00000384200.4	Q13976-1

Frequencies

GnomAD3 genomes AF: 0.00462 AC: 699 AN: 151142 Hom.: 3 Cov.: 31

Gnomad AFR AF: 0.0162

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00112

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000886

Gnomad OTH AF: 0.00384

GnomAD4 exome AF: 0.000412 AC: 178 AN: 431576 Hom.: 2 AF XY: 0.000396 AC XY: 81 AN XY: 204696

African (AFR) AF: 0.0199 AC: 155 AN: 7782

American (AMR) AF: 0.000924 AC: 1 AN: 1082

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2822

East Asian (EAS) AF: 0.00 AC: 0 AN: 2214

South Asian (SAS) AF: 0.00 AC: 0 AN: 8486

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4950

Middle Eastern (MID) AF: 0.00341 AC: 3 AN: 880

European-Non Finnish (NFE) AF: 0.0000180 AC: 7 AN: 388996

Other (OTH) AF: 0.000835 AC: 12 AN: 14364

GnomAD4 genome AF: 0.00462 AC: 699 AN: 151252 Hom.: 3 Cov.: 31 AF XY: 0.00425 AC XY: 314 AN XY: 73900

African (AFR) AF: 0.0161 AC: 667 AN: 41390

American (AMR) AF: 0.00112 AC: 17 AN: 15178

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5116

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10280

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000886 AC: 6 AN: 67692

Other (OTH) AF: 0.00380 AC: 8 AN: 2104

Alfa AF: 0.00415 Hom.: 0

Bravo AF: 0.00547

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	16
DANN	Benign	0.95
PhyloP100		0.63
Mutation Taster		=100/0	polymorphism

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: rs183264171; hg19: chr10-52751538;