10-52251592-T-C

Variant names:

• chr10-52251592-T-C
• NM_006258.4:c.1099T>C

Variant summary

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

The NM_006258.4(PRKG1):​c.1099T>C​(p.Phe367Leu) 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 (★). Synonymous variant affecting the same amino acid position (i.e. F367F) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PRKG1 NM_006258.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.48
• 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-AS1 (HGNC:45029): (PRKG1 antisense RNA 1)

LOC124902425 (HGNC:):

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKG1	NM_006258.4	MANE Select	c.1099T>C	p.Phe367Leu	missense	Exon 10 of 18	NP_006249.1	Q13976-2
	PRKG1	NM_001098512.3		c.1054T>C	p.Phe352Leu	missense	Exon 10 of 18	NP_001091982.1	Q13976-1
	PRKG1	NM_001374781.1		c.-111T>C		5_prime_UTR	Exon 6 of 14	NP_001361710.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKG1	ENST00000373980.11	TSL:1 MANE Select	c.1099T>C	p.Phe367Leu	missense	Exon 10 of 18	ENSP00000363092.5	Q13976-2
	PRKG1	ENST00000401604.8	TSL:5	c.1054T>C	p.Phe352Leu	missense	Exon 10 of 18	ENSP00000384200.4	Q13976-1
	PRKG1	ENST00000672084.1		c.250T>C	p.Phe84Leu	missense	Exon 4 of 11	ENSP00000499822.1	A0A5F9ZGW0

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Aortic aneurysm, familial thoracic 8 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.67	D
Eigen	Benign	0.064
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.014	T
MetaRNN	Uncertain	0.54	D
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.0	N
PhyloP100		7.5
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-4.1	D
REVEL	Uncertain	0.39
Sift	Benign	0.091	T
Sift4G	Benign	0.27	T
Polyphen		0.17	B
Vest4		0.69
MutPred		0.42		Gain of helix (P = 0.062)
MVP		0.71
MPC		0.81
ClinPred		0.94	D
GERP RS		6.1
Varity_R		0.80
gMVP		0.80
Mutation Taster		=22/78	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

hg19: chr10-54011352;