10-51153171-G-C

Position:

• chr10-51153171-G-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2 BP4 BS2

The NM_006258.4(PRKG1):​c.319G>C​(p.Asp107His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000959 in 1,459,276 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: 31)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: PRKG1 NM_006258.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 9.28

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 Likely_benign. Variant got -4 ACMG points.

• 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=0.30323997).
• BS2: High AC in GnomAdExome4 at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRKG1	NM_006258.4	c.319G>C	p.Asp107His	missense_variant	2/18	ENST00000373980.11	NP_006249.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRKG1	ENST00000373980.11	c.319G>C	p.Asp107His	missense_variant	2/18	1	NM_006258.4	ENSP00000363092.5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000800 AC: 2 AN: 250072 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135192

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000656

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000959 AC: 14 AN: 1459276 Hom.: 0 Cov.: 30 AF XY: 0.0000152 AC XY: 11 AN XY: 725964

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000929

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.0000498

GnomAD4 genome Cov.: 31

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Aortic aneurysm, familial thoracic 8 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 27, 2017	This sequence change replaces aspartic acid with histidine at codon 107 of the PRKG1 protein (p.Asp107His). The aspartic acid residue is weakly conserved and there is a moderate physicochemical difference between aspartic acid and histidine. This variant is present in population databases (rs751916382, ExAC 0.01%) but has not been reported in the literature in individuals with a PRKG1-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 03, 2019	- -

PRKG1-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 09, 2023

The PRKG1 c.319G>C variant is predicted to result in the amino acid substitution p.Asp107His. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0066% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/10-52912931-G-C). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Familial thoracic aortic aneurysm and aortic dissection Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 30, 2018

The p.D107H variant (also known as c.319G>C), located in coding exon 2 of the PRKG1 gene, results from a G to C substitution at nucleotide position 319. The aspartic acid at codon 107 is replaced by histidine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Feb 08, 2019

Not observed at a significant frequency in large population cohorts (Lek et al., 2016).; In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; D107H reported as a variant of uncertain significance by another laboratory in ClinVar (SCV000659233.1; Landrum et al., 2016).; The D107H variant has not been published as pathogenic or been reported as benign to our knowledge. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.0096	T
BayesDel_noAF	Uncertain	-0.070
CADD	Pathogenic	27
DANN	Uncertain	0.98
DEOGEN2	Benign	0.35	T;T;.;.;.;.;.;.
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.94	.;D;D;.;D;D;D;D
M_CAP	Benign	0.080	D
MetaRNN	Benign	0.30	T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.57	D
MutationAssessor	Benign	0.90	L;L;.;.;.;.;.;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-2.1	N;.;.;.;N;.;.;.
REVEL	Uncertain	0.44
Sift	Benign	0.15	T;.;.;.;T;.;.;.
Sift4G	Benign	0.096	.;T;.;.;T;.;.;.
Polyphen		0.24	B;B;.;B;B;.;.;.
Vest4		0.36, 0.38
MutPred		0.27		Gain of methylation at K91 (P = 0.0515);Gain of methylation at K91 (P = 0.0515);.;.;.;.;.;.;
MVP		0.63
MPC		0.75
ClinPred		0.29	T
GERP RS		5.8
Varity_R		0.46
gMVP		0.66

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: rs751916382; hg19: chr10-52912931;