10-50991034-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001098512.3(PRKG1):c.-345A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0159 in 226,654 control chromosomes in the GnomAD database, including 54 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.018 (40 hom., cov: 28)
  • Exomes 𝑓: 0.011 (14 hom.)
• Consequence: PRKG1 NM_001098512.3 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.335

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 10-50991034-A-G is Benign according to our data. Variant chr10-50991034-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 674059.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0184 (2764/150512) while in subpopulation SAS AF= 0.0355 (166/4682). AF 95% confidence interval is 0.0334. There are 40 homozygotes in gnomad4. There are 1317 alleles in male gnomad4 subpopulation. Median coverage is 28. This position pass quality control queck.
• BS2: High AC in GnomAd at 2747 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRKG1	NM_001098512.3	c.-345A>G		5_prime_UTR_variant	1/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKG1	ENST00000401604.8	c.-345A>G		5_prime_UTR_variant	1/18	5		P1

Frequencies

GnomAD3 genomes AF: 0.0183 AC: 2747 AN: 150396 Hom.: 39 Cov.: 28

Gnomad AFR AF: 0.0346

Gnomad AMI AF: 0.00549

Gnomad AMR AF: 0.0113

Gnomad ASJ AF: 0.0235

Gnomad EAS AF: 0.000195

Gnomad SAS AF: 0.0354

Gnomad FIN AF: 0.00643

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0120

Gnomad OTH AF: 0.0175

GnomAD4 exome AF: 0.0110 AC: 839 AN: 76142 Hom.: 14 Cov.: 0 AF XY: 0.0127 AC XY: 513 AN XY: 40530

Gnomad4 AFR exome AF: 0.0341

Gnomad4 AMR exome AF: 0.00647

Gnomad4 ASJ exome AF: 0.0205

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0241

Gnomad4 FIN exome AF: 0.00564

Gnomad4 NFE exome AF: 0.00856

Gnomad4 OTH exome AF: 0.0106

GnomAD4 genome AF: 0.0184 AC: 2764 AN: 150512 Hom.: 40 Cov.: 28 AF XY: 0.0179 AC XY: 1317 AN XY: 73532

Gnomad4 AFR AF: 0.0349

Gnomad4 AMR AF: 0.0113

Gnomad4 ASJ AF: 0.0235

Gnomad4 EAS AF: 0.000196

Gnomad4 SAS AF: 0.0355

Gnomad4 FIN AF: 0.00643

Gnomad4 NFE AF: 0.0120

Gnomad4 OTH AF: 0.0173

Alfa AF: 0.0158 Hom.: 4

Bravo AF: 0.0207

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 19, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
Cadd	Benign	12
Dann	Benign	0.57

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs186127402; hg19: chr10-52750794;