10-50991227-A-G

Position:

• chr10-50991227-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001098512.3(PRKG1):​c.-152A>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 0.0131 in 1,162,506 control chromosomes in the GnomAD database, including 239 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (49 hom., cov: 29)
  • Exomes 𝑓: 0.012 (190 hom.)
• Consequence: PRKG1 NM_001098512.3 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0580

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 10-50991227-A-G is Benign according to our data. Variant chr10-50991227-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 676360.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0194 (2943/152070) while in subpopulation AFR AF= 0.0421 (1748/41492). AF 95% confidence interval is 0.0405. There are 49 homozygotes in gnomad4. There are 1432 alleles in male gnomad4 subpopulation. Median coverage is 29. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 2943 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRKG1	NM_001098512.3	c.-152A>G		5_prime_UTR_variant	1/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKG1	ENST00000401604.8	c.-152A>G		5_prime_UTR_variant	1/18	5		P1

Frequencies

GnomAD3 genomes AF: 0.0193 AC: 2932 AN: 151954 Hom.: 49 Cov.: 29

Gnomad AFR AF: 0.0420

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0147

Gnomad ASJ AF: 0.00404

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0106

Gnomad FIN AF: 0.000755

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0121

Gnomad OTH AF: 0.0221

GnomAD4 exome AF: 0.0121 AC: 12269 AN: 1010436 Hom.: 190 Cov.: 13 AF XY: 0.0122 AC XY: 6160 AN XY: 502864

Gnomad4 AFR exome AF: 0.0405

Gnomad4 AMR exome AF: 0.0122

Gnomad4 ASJ exome AF: 0.00497

Gnomad4 EAS exome AF: 0.0000361

Gnomad4 SAS exome AF: 0.0156

Gnomad4 FIN exome AF: 0.00104

Gnomad4 NFE exome AF: 0.0123

Gnomad4 OTH exome AF: 0.0135

GnomAD4 genome AF: 0.0194 AC: 2943 AN: 152070 Hom.: 49 Cov.: 29 AF XY: 0.0193 AC XY: 1432 AN XY: 74340

Gnomad4 AFR AF: 0.0421

Gnomad4 AMR AF: 0.0147

Gnomad4 ASJ AF: 0.00404

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0110

Gnomad4 FIN AF: 0.000755

Gnomad4 NFE AF: 0.0121

Gnomad4 OTH AF: 0.0218

Alfa AF: 0.0144 Hom.: 2

Bravo AF: 0.0216

Asia WGS AF: 0.00895 AC: 31 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 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	-0.81
CADD	Benign	1.7
DANN	Benign	0.50

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs111417107; hg19: chr10-52750987;