chr10-51153273-A-G

Variant names:

• chr10-51153273-A-G
• rs761759814
• NM_006258.4:c.421A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_006258.4(PRKG1):​c.421A>G​(p.Lys141Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K141Q) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: PRKG1 NM_006258.4 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:2
• Conservation: PhyloP100: 8.64
• Publications: 2 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006258.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKG1	NM_006258.4	MANE Select	c.421A>G	p.Lys141Glu	missense	Exon 2 of 18	NP_006249.1
	PRKG1	NM_001098512.3		c.376A>G	p.Lys126Glu	missense	Exon 2 of 18	NP_001091982.1
	PRKG1	NM_001374782.1		c.421A>G	p.Lys141Glu	missense	Exon 2 of 7	NP_001361711.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKG1	ENST00000373980.11	TSL:1 MANE Select	c.421A>G	p.Lys141Glu	missense	Exon 2 of 18	ENSP00000363092.5
	PRKG1	ENST00000401604.8	TSL:5	c.376A>G	p.Lys126Glu	missense	Exon 2 of 18	ENSP00000384200.4
	PRKG1	ENST00000645324.1		c.421A>G	p.Lys141Glu	missense	Exon 2 of 8	ENSP00000494124.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: no assertion criteria provided

Submissions by phenotype

not provided Uncertain:2

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.54	D
Eigen	Benign	0.028
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.093	D
MetaRNN	Uncertain	0.61	D
MetaSVM	Uncertain	0.41	D
MutationAssessor	Benign	1.4	L
PhyloP100		8.6
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.55
Sift	Benign	0.43	T
Sift4G	Benign	0.82	T
Polyphen		0.085	B
Vest4		0.69
MutPred		0.45		Loss of methylation at K126 (P = 0.0135)
MVP		0.93
MPC		0.89
ClinPred		0.79	D
GERP RS		5.5
Varity_R		0.77
gMVP		0.98
Mutation Taster		=47/53	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: rs761759814; hg19: chr10-52913033;