10-52280794-C-T

Position:

• chr10-52280794-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PM2 PP2 BP4 BS2

The NM_006258.4(PRKG1):​c.1409C>T​(p.Ser470Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,460,450 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: PRKG1 NM_006258.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.93

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]

PRKG1-AS1 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PRKG1. . Gene score misZ 2.982 (greater than the threshold 3.09). Trascript score misZ 3.8719 (greater than threshold 3.09). GenCC has associacion of gene with familial thoracic aortic aneurysm and aortic dissection, aortic aneurysm, familial thoracic 8.
• BP4: Computational evidence support a benign effect (MetaRNN=0.3973269).
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRKG1	NM_006258.4	c.1409C>T	p.Ser470Leu	missense_variant	13/18	ENST00000373980.11	NP_006249.1
PRKG1	NM_001098512.3	c.1364C>T	p.Ser455Leu	missense_variant	13/18		NP_001091982.1
PRKG1	NM_001374781.1	c.200C>T	p.Ser67Leu	missense_variant	9/14		NP_001361710.1
PRKG1	XM_017016413.2	c.1106C>T	p.Ser369Leu	missense_variant	13/18		XP_016871902.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRKG1	ENST00000373980.11	c.1409C>T	p.Ser470Leu	missense_variant	13/18	1	NM_006258.4	ENSP00000363092.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1460450 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726566

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Aortic aneurysm, familial thoracic 8 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 04, 2023

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 470 of the PRKG1 protein (p.Ser470Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PRKG1-related conditions. ClinVar contains an entry for this variant (Variation ID: 77987). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 24, 2024

Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Benign	-0.0079	T
BayesDel_noAF	Benign	-0.25
CADD	Pathogenic	27
DANN	Uncertain	0.98
DEOGEN2	Benign	0.34	T;T;.;.
Eigen	Benign	-0.028
Eigen_PC	Benign	0.17
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	.;D;.;D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.40	T;T;T;T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	0.45	N;N;.;.
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.1	D;.;.;D
REVEL	Benign	0.18
Sift	Benign	0.61	T;.;.;T
Sift4G	Benign	0.64	.;T;.;T
Polyphen		0.66	P;P;P;P
Vest4		0.77, 0.79
MutPred		0.50		Loss of disorder (P = 0.0055);Loss of disorder (P = 0.0055);.;.;
MVP		0.45
MPC		0.68
ClinPred		0.82	D
GERP RS		5.5
Varity_R		0.55
gMVP		0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs267602521; hg19: chr10-54040554; COSMIC: COSV64770029;