10-50991328-C-CGCT

Variant names:

• chr10-50991328-C-CGCT
• rs35361017
• NM_001098512.3:c.-49_-48insTGC

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_001098512.3(PRKG1):​c.-49_-48insTGC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.237 in 1,476,694 control chromosomes in the GnomAD database, including 38,643 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.24 (4524 hom., cov: 23)
  • Exomes 𝑓: 0.24 (34119 hom.)
• Consequence: PRKG1 NM_001098512.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.205
• 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, Unknown Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP6: Variant 10-50991328-C-CGCT is Benign according to our data. Variant chr10-50991328-C-CGCT is described in ClinVar as Benign. ClinVar VariationId is 1266074.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.369 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKG1	NM_001098512.3		c.-49_-48insTGC		5_prime_UTR	Exon 1 of 18	NP_001091982.1	Q13976-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKG1	ENST00000401604.8	TSL:5	c.-49_-48insTGC		5_prime_UTR	Exon 1 of 18	ENSP00000384200.4	Q13976-1

Frequencies

GnomAD3 genomes AF: 0.237 AC: 35897 AN: 151432 Hom.: 4527 Cov.: 23

Gnomad AFR AF: 0.184

Gnomad AMI AF: 0.207

Gnomad AMR AF: 0.300

Gnomad ASJ AF: 0.208

Gnomad EAS AF: 0.383

Gnomad SAS AF: 0.196

Gnomad FIN AF: 0.233

Gnomad MID AF: 0.170

Gnomad NFE AF: 0.250

Gnomad OTH AF: 0.244

GnomAD4 exome AF: 0.237 AC: 314042 AN: 1325150 Hom.: 34119 Cov.: 35 AF XY: 0.234 AC XY: 152830 AN XY: 652590

African (AFR) AF: 0.170 AC: 4420 AN: 26002

American (AMR) AF: 0.214 AC: 5277 AN: 24688

Ashkenazi Jewish (ASJ) AF: 0.187 AC: 4154 AN: 22218

East Asian (EAS) AF: 0.345 AC: 10432 AN: 30218

South Asian (SAS) AF: 0.166 AC: 11832 AN: 71384

European-Finnish (FIN) AF: 0.232 AC: 10755 AN: 46264

Middle Eastern (MID) AF: 0.153 AC: 738 AN: 4820

European-Non Finnish (NFE) AF: 0.243 AC: 253501 AN: 1045176

Other (OTH) AF: 0.238 AC: 12933 AN: 54380

GnomAD4 genome AF: 0.237 AC: 35896 AN: 151544 Hom.: 4524 Cov.: 23 AF XY: 0.236 AC XY: 17474 AN XY: 74006

African (AFR) AF: 0.184 AC: 7588 AN: 41340

American (AMR) AF: 0.300 AC: 4570 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.208 AC: 720 AN: 3468

East Asian (EAS) AF: 0.383 AC: 1939 AN: 5058

South Asian (SAS) AF: 0.198 AC: 950 AN: 4792

European-Finnish (FIN) AF: 0.233 AC: 2449 AN: 10494

Middle Eastern (MID) AF: 0.161 AC: 47 AN: 292

European-Non Finnish (NFE) AF: 0.250 AC: 16933 AN: 67836

Other (OTH) AF: 0.243 AC: 512 AN: 2110

Alfa AF: 0.0853 Hom.: 127

ClinVar

ClinVar submissions

Significance: 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
PhyloP100		0.20
Mutation Taster		=300/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs35361017; hg19: chr10-52751088;