PRKG2

protein-coding

protein kinase cGMP-dependent 2, the group of AGC family kinases

Gene summary

This gene encodes a protein that belongs to the serine/threonine protein kinase family of proteins. The encoded protein binds to and inhibits the activation of several receptor tyrosine kinases. The membrane-bound protein is a regulator of intestinal secretion, bone growth and renin secretion. Alternate splicing results in multiple transcript variants encoding distinct isoforms whose regulatory N-termini differ in length but whose C-terminal catalytic domains are identical. [provided by RefSeq, May 2018]

MANE transcript

NM_006259.3

Inheritance

ClinVar variants

P:10U:67B:8

Top phenotype

Spondylometaphyseal dysplasia, Pagnamenta type; Acromesomelic dysplasia 4

gnomAD constraint

pLI —, LoF o/e 0.21

Max pathogenic AF

—

Genomic locus

chr4:81,087,370-81,215,222

External References & Databases

Ensembl (ENSG00000138669)

Transcript & Mutation Effects

hg38 • Region Span ~127.9 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

acromesomelic dysplasia 4STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0030553

Submitter: G2P

acromesomelic dysplasia 4STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0030553

Submitter: Labcorp Genetics (formerly Invitae)

spondylometaphyseal dysplasia, pagnamenta typeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0030487

Submitter: PanelApp Australia

acromesomelic dysplasia 4STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0030553

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Spondylometaphyseal dysplasia, Pagnamenta type; Acromesomelic dysplasia 4AR

Manifestation: Craniofacial; Musculoskeletal

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 33106379; 34782440

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PRKG2 variants in ClinVar

6 Conditions Cataloged

Inborn genetic diseasesTotal: 54

not specifiedTotal: 15

PRKG2-related disorderTotal: 8

Acromesomelic dysplasia 4Total: 7

not providedTotal: 3

Spondylometaphyseal dysplasia, pagnamenta typeTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_006259.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			2 clinvar	6 clinvar	1 clinvar	9
missense		2 clinvar	60 clinvar	1 clinvar		63
nonsense	3 clinvar		2 clinvar			5
start loss						0
frameshift	3 clinvar	1 clinvar				4
splice donor/acceptor (+/-2bp)	1 clinvar		3 clinvar			4
Total	7	3	67	7	1	85

Highest pathogenic variant AF is 0.0000013700788

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 46 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_006259.3	RefSeq	NP_006250.1	18	MANE Select
ENST00000264399.6	Ensembl	ENSP00000264399.1	18	MANE Select
NM_001282480.1	RefSeq	NP_001269409.1	9	Standard
NM_001282481.1	RefSeq	NP_001269410.1	9	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Platelet activation - Homo sapiens (human)
Regulation of lipolysis in adipocytes - Homo sapiens (human)
Long-term depression - Homo sapiens (human)
Gap junction - Homo sapiens (human)
Circadian entrainment - Homo sapiens (human)

Biological Process

protein phosphorylation
signal transduction
peptidyl-serine autophosphorylation
cofactor metabolic process
protein localization to plasma membrane

Molecular Function

protein kinase activity
cGMP-dependent protein kinase activity
ATP binding
cGMP binding
protein homodimerization activity

Cellular Component

cytosol
apical plasma membrane
nuclear membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000395578
Coding exons: 18
Length: 126382
Individuals with no LoFs: 125731
Homozygous LoFs: 0
Heterozygous LoFs: 17
Defined: 125748
p: 0.0000676

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.99	231	399	0.579	0.0000202	5006
Missense (PolyPhen)		60	146	0.41096		1851
Synonymous	-0.708	156	145	1.07	0.00000712	1416
Loss of Function	4.79	9	42.9	0.210	0.00000220	532

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00011	0.00011	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.000062	0.000062	rare
South Asian	0.00013	0.00013	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Crucial regulator of intestinal secretion and bone growth (By similarity). Phosphorylates and activates CFTR on the plasma membrane. Plays a key role in intestinal secretion by regulating cGMP-dependent translocation of CFTR in jejunum (By similarity). Acts downstream of NMDAR to activate the plasma membrane accumulation of GRIA1/GLUR1 in synapse and increase synaptic plasticity. Phosphorylates GRIA1/GLUR1 at Ser-863 (By similarity). Acts as regulator of gene expression and activator of the extracellular signal-regulated kinases MAPK3/ERK1 and MAPK1/ERK2 in mechanically stimulated osteoblasts. Under fluid shear stress, mediates ERK activation and subsequent induction of FOS, FOSL1/FRA1, FOSL2/FRA2 and FOSB that play a key role in the osteoblast anabolic response to mechanical stimulation (By similarity). {ECO:0000250|UniProtKB:Q61410, ECO:0000250|UniProtKB:Q64595}.;

Recessive Scores

pRec: 0.223

Intolerance Scores

LoFtool: 0.219
RVIS EVS: -0.84
RVIS percentile EVS: 11.18

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Indispensability pred.: E
Indispensability score: 0.834

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium