10-50991310-AGCCGCCGCCGCCGCCGCCGCCGCC-AGCCGCCGCCGCCGCCGCC

Variant names:

• chr10-50991310-AGCCGCC-A
• rs79957958
• NM_001098512.3:c.-41_-36delGCCGCC

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_001098512.3(PRKG1):​c.-41_-36delGCCGCC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000677 in 1,396,968 control chromosomes in the GnomAD database, including 8 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00059 (8 hom.)
• Consequence: PRKG1 NM_001098512.3 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.62
• Publications: 3 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: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAd4 at 207 AD,Unknown 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.-41_-36delGCCGCC		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.-41_-36delGCCGCC		5_prime_UTR	Exon 1 of 18	ENSP00000384200.4	Q13976-1

Frequencies

GnomAD3 genomes AF: 0.00144 AC: 207 AN: 143816 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00326

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00106

Gnomad ASJ AF: 0.000594

Gnomad EAS AF: 0.000909

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000103

Gnomad MID AF: 0.00327

Gnomad NFE AF: 0.000767

Gnomad OTH AF: 0.00306

GnomAD4 exome AF: 0.000590 AC: 739 AN: 1253054 Hom.: 8 AF XY: 0.000562 AC XY: 347 AN XY: 617556

African (AFR) AF: 0.00271 AC: 59 AN: 21798

American (AMR) AF: 0.000808 AC: 19 AN: 23516

Ashkenazi Jewish (ASJ) AF: 0.0000493 AC: 1 AN: 20290

East Asian (EAS) AF: 0.000698 AC: 20 AN: 28664

South Asian (SAS) AF: 0.000713 AC: 48 AN: 67286

European-Finnish (FIN) AF: 0.000495 AC: 22 AN: 44432

Middle Eastern (MID) AF: 0.000481 AC: 2 AN: 4154

European-Non Finnish (NFE) AF: 0.000522 AC: 518 AN: 991598

Other (OTH) AF: 0.000974 AC: 50 AN: 51316

GnomAD4 genome AF: 0.00144 AC: 207 AN: 143914 Hom.: 0 Cov.: 0 AF XY: 0.00146 AC XY: 102 AN XY: 69878

African (AFR) AF: 0.00325 AC: 128 AN: 39370

American (AMR) AF: 0.00106 AC: 15 AN: 14168

Ashkenazi Jewish (ASJ) AF: 0.000594 AC: 2 AN: 3366

East Asian (EAS) AF: 0.000912 AC: 4 AN: 4384

South Asian (SAS) AF: 0.00 AC: 0 AN: 4536

European-Finnish (FIN) AF: 0.000103 AC: 1 AN: 9738

Middle Eastern (MID) AF: 0.00352 AC: 1 AN: 284

European-Non Finnish (NFE) AF: 0.000767 AC: 50 AN: 65218

Other (OTH) AF: 0.00303 AC: 6 AN: 1982

Alfa AF: 0.00265 Hom.: 279

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.6
Mutation Taster		=300/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs79957958; hg19: chr10-52751070; COSMIC: COSV100917311;