chr10-52054541-T-C

Variant names:

• chr10-52054541-T-C
• rs1554797637
• NM_006258.4:c.820T>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_006258.4(PRKG1):​c.820T>C​(p.Phe274Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PRKG1 NM_006258.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.67
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• aortic aneurysm, familial thoracic 8

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.909

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKG1	NM_006258.4	c.820T>C	p.Phe274Leu	missense_variant	Exon 6 of 18	ENST00000373980.11	NP_006249.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRKG1	ENST00000373980.11	c.820T>C	p.Phe274Leu	missense_variant	Exon 6 of 18	1	NM_006258.4	ENSP00000363092.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Aortic aneurysm, familial thoracic 8 Uncertain:1

Mar 01, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. 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: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a PRKG1-related disease. This sequence change replaces phenylalanine with leucine at codon 274 of the PRKG1 protein (p.Phe274Leu). The phenylalanine residue is moderately conserved and there is a small physicochemical difference between phenylalanine and leucine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.97	D;D;.;.;.;.
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	.;D;D;.;D;D
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.7	M;M;.;.;.;.
PhyloP100		7.7
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-5.4	D;.;.;.;D;.
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0020	D;.;.;.;D;.
Sift4G	Uncertain	0.0060	.;D;.;.;D;.
Polyphen		0.99	D;D;.;D;D;.
Vest4		0.92, 0.90
MutPred		0.69		Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);.;.;.;.;
MVP		0.92
MPC		1.6
ClinPred		0.99	D
GERP RS		6.1
Varity_R		0.96
gMVP		0.82
Mutation Taster		=34/66	disease causing

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

Other links and lift over

dbSNP: rs1554797637; hg19: chr10-53814301;