rs267602521

Variant names:

• chr10-52280794-C-T
• rs267602521
• NM_006258.4:c.1409C>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 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 (★★). Synonymous variant affecting the same amino acid position (i.e. S470S) has been classified as Likely benign.

• 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:3
• Conservation: PhyloP100: 4.93
• Publications: 4 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)

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3973269).
• BS2: High AC in GnomAdExome4 at 5 AD gene.

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.1409C>T	p.Ser470Leu	missense	Exon 13 of 18	NP_006249.1
	PRKG1	NM_001098512.3		c.1364C>T	p.Ser455Leu	missense	Exon 13 of 18	NP_001091982.1
	PRKG1	NM_001374781.1		c.200C>T	p.Ser67Leu	missense	Exon 9 of 14	NP_001361710.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKG1	ENST00000373980.11	TSL:1 MANE Select	c.1409C>T	p.Ser470Leu	missense	Exon 13 of 18	ENSP00000363092.5
	PRKG1-AS1	ENST00000426785.2	TSL:1	n.169+13121G>A		intron	N/A
	PRKG1	ENST00000401604.8	TSL:5	c.1364C>T	p.Ser455Leu	missense	Exon 13 of 18	ENSP00000384200.4

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

African (AFR) AF: 0.0000299 AC: 1 AN: 33438

American (AMR) AF: 0.00 AC: 0 AN: 44666

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26104

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39658

South Asian (SAS) AF: 0.00 AC: 0 AN: 86124

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53334

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111034

Other (OTH) AF: 0.00 AC: 0 AN: 60332

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Aortic aneurysm, familial thoracic 8 (1)
-	1	-	Familial thoracic aortic aneurysm and aortic dissection (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.028
Eigen_PC	Benign	0.17
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.40	T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	0.45	N
PhyloP100		4.9
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.18
Sift	Benign	0.61	T
Sift4G	Benign	0.64	T
Polyphen		0.66	P
Vest4		0.77
MutPred		0.50		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
Mutation Taster		=35/65	disease causing

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

Other links and lift over

dbSNP: rs267602521; hg19: chr10-54040554; COSMIC: COSV64770029;