rs45615337

Positions:

• chr10-51467714-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000373980.11(PRKG1):​c.479-9C>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0433 in 1,596,146 control chromosomes in the GnomAD database, including 2,563 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.080 (894 hom., cov: 32)
  • Exomes 𝑓: 0.039 (1669 hom.)
• Consequence: PRKG1 ENST00000373980.11 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00001982
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.59

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=-0.85).
• BP6: Variant 10-51467714-C-T is Benign according to our data. Variant chr10-51467714-C-T is described in ClinVar as [Benign]. Clinvar id is 381780.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-51467714-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.193 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRKG1	NM_006258.4	c.479-9C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000373980.11	NP_006249.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRKG1	ENST00000373980.11	c.479-9C>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_006258.4	ENSP00000363092

Frequencies

GnomAD3 genomes AF: 0.0799 AC: 12125 AN: 151758 Hom.: 891 Cov.: 32

Gnomad AFR AF: 0.197

Gnomad AMI AF: 0.123

Gnomad AMR AF: 0.0406

Gnomad ASJ AF: 0.0263

Gnomad EAS AF: 0.00521

Gnomad SAS AF: 0.0234

Gnomad FIN AF: 0.0405

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0360

Gnomad OTH AF: 0.0681

GnomAD3 exomes AF: 0.0409 AC: 10205 AN: 249554 Hom.: 470 AF XY: 0.0371 AC XY: 5005 AN XY: 134810

Gnomad AFR exome AF: 0.200

Gnomad AMR exome AF: 0.0245

Gnomad ASJ exome AF: 0.0251

Gnomad EAS exome AF: 0.00240

Gnomad SAS exome AF: 0.0225

Gnomad FIN exome AF: 0.0433

Gnomad NFE exome AF: 0.0355

Gnomad OTH exome AF: 0.0359

GnomAD4 exome AF: 0.0394 AC: 56909 AN: 1444270 Hom.: 1669 Cov.: 27 AF XY: 0.0381 AC XY: 27416 AN XY: 719494

Gnomad4 AFR exome AF: 0.204

Gnomad4 AMR exome AF: 0.0261

Gnomad4 ASJ exome AF: 0.0250

Gnomad4 EAS exome AF: 0.0111

Gnomad4 SAS exome AF: 0.0233

Gnomad4 FIN exome AF: 0.0430

Gnomad4 NFE exome AF: 0.0372

Gnomad4 OTH exome AF: 0.0444

GnomAD4 genome AF: 0.0799 AC: 12137 AN: 151876 Hom.: 894 Cov.: 32 AF XY: 0.0781 AC XY: 5803 AN XY: 74272

Gnomad4 AFR AF: 0.197

Gnomad4 AMR AF: 0.0405

Gnomad4 ASJ AF: 0.0263

Gnomad4 EAS AF: 0.00522

Gnomad4 SAS AF: 0.0232

Gnomad4 FIN AF: 0.0405

Gnomad4 NFE AF: 0.0360

Gnomad4 OTH AF: 0.0674

Alfa AF: 0.0537 Hom.: 289

Bravo AF: 0.0851

Asia WGS AF: 0.0330 AC: 114 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 21, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 28, 2016	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. -

Aortic aneurysm, familial thoracic 8 Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Jan 03, 2023

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.46
DANN	Benign	0.26

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000020
dbscSNV1_RF	Benign	0.0
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: rs45615337; hg19: chr10-53227474;