10-50991696-G-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001098512.3(PRKG1):c.266+52G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00317 in 1,224,034 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0028 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0032 (15 hom.)
• Consequence: PRKG1 NM_001098512.3 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.113

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 10-50991696-G-C is Benign according to our data. Variant chr10-50991696-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 1219572.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 419 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRKG1	NM_001098512.3	c.266+52G>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKG1	ENST00000401604.8	c.266+52G>C		intron_variant		5		P1

Frequencies

GnomAD3 genomes AF: 0.00278 AC: 419 AN: 150512 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000582

Gnomad AMI AF: 0.00220

Gnomad AMR AF: 0.000397

Gnomad ASJ AF: 0.00116

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.0127

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00367

Gnomad OTH AF: 0.00193

GnomAD4 exome AF: 0.00323 AC: 3467 AN: 1073414 Hom.: 15 AF XY: 0.00332 AC XY: 1704 AN XY: 512614

Gnomad4 AFR exome AF: 0.000582

Gnomad4 AMR exome AF: 0.000611

Gnomad4 ASJ exome AF: 0.000906

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00222

Gnomad4 FIN exome AF: 0.0113

Gnomad4 NFE exome AF: 0.00319

Gnomad4 OTH exome AF: 0.00240

GnomAD4 genome AF: 0.00278 AC: 419 AN: 150620 Hom.: 1 Cov.: 32 AF XY: 0.00318 AC XY: 234 AN XY: 73576

Gnomad4 AFR AF: 0.000581

Gnomad4 AMR AF: 0.000397

Gnomad4 ASJ AF: 0.00116

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.0127

Gnomad4 NFE AF: 0.00367

Gnomad4 OTH AF: 0.00191

Alfa AF: 0.00255 Hom.: 0

Bravo AF: 0.00179

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

Jul 26, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
Cadd	Benign	4.5
Dann	Benign	0.89

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

Publications

LitVar

Other links and lift over

dbSNP: rs555654395; hg19: chr10-52751456;