rs56047641

chr10-52161895-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_006258.4(PRKG1):c.1008T>C(p.Phe336=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.012 in 1,612,610 control chromosomes in the GnomAD database, including 1,135 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.049 (515 hom., cov: 33)
  • Exomes 𝑓: 0.0082 (620 hom.)
• Consequence: PRKG1 NM_006258.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.10

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 10-52161895-T-C is Benign according to our data. Variant chr10-52161895-T-C is described in ClinVar as [Benign]. Clinvar id is 263888.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-52161895-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=2.1 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.156 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRKG1	NM_006258.4	c.1008T>C	p.Phe336=	synonymous_variant	9/18	ENST00000373980.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKG1	ENST00000373980.11	c.1008T>C	p.Phe336=	synonymous_variant	9/18	1	NM_006258.4

Frequencies

GnomAD3 genomes AF: 0.0489 AC: 7434 AN: 152036 Hom.: 514 Cov.: 33

Gnomad AFR AF: 0.160

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0158

Gnomad ASJ AF: 0.000866

Gnomad EAS AF: 0.0594

Gnomad SAS AF: 0.0273

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000780

Gnomad OTH AF: 0.0406

GnomAD3 exomes AF: 0.0202 AC: 5070 AN: 250492 Hom.: 281 AF XY: 0.0178 AC XY: 2406 AN XY: 135396

Gnomad AFR exome AF: 0.166

Gnomad AMR exome AF: 0.00774

Gnomad ASJ exome AF: 0.00119

Gnomad EAS exome AF: 0.0588

Gnomad SAS exome AF: 0.0295

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000486

Gnomad OTH exome AF: 0.0116

GnomAD4 exome AF: 0.00820 AC: 11973 AN: 1460456 Hom.: 620 Cov.: 31 AF XY: 0.00820 AC XY: 5955 AN XY: 726532

Gnomad4 AFR exome AF: 0.165

Gnomad4 AMR exome AF: 0.00906

Gnomad4 ASJ exome AF: 0.00119

Gnomad4 EAS exome AF: 0.0530

Gnomad4 SAS exome AF: 0.0287

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.000378

Gnomad4 OTH exome AF: 0.0164

GnomAD4 genome AF: 0.0490 AC: 7448 AN: 152154 Hom.: 515 Cov.: 33 AF XY: 0.0485 AC XY: 3607 AN XY: 74402

Gnomad4 AFR AF: 0.160

Gnomad4 AMR AF: 0.0158

Gnomad4 ASJ AF: 0.000866

Gnomad4 EAS AF: 0.0588

Gnomad4 SAS AF: 0.0275

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000780

Gnomad4 OTH AF: 0.0402

Alfa AF: 0.0193 Hom.: 122

Bravo AF: 0.0563

Asia WGS AF: 0.0570 AC: 197 AN: 3476

EpiCase AF: 0.000872

EpiControl AF: 0.000652

ClinVar

Significance: Benign

Submissions summary: Benign:5

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	Apr 09, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 20, 2016	- -

Familial thoracic aortic aneurysm and aortic dissection Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 03, 2015	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Dec 01, 2022	- -

Aortic aneurysm, familial thoracic 8 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
Cadd	Benign	9.0
Dann	Benign	0.75

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: rs56047641; hg19: chr10-53921655; COSMIC: COSV64776418;