4-81135195-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_006259.3(PRKG2):​c.1736C>T​(p.Pro579Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000343 in 1,458,104 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

PRKG2
NM_006259.3 missense

Scores

10
5
4

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.88
Variant links:
Genes affected
PRKG2 (HGNC:9416): (protein kinase cGMP-dependent 2) 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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.972

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PRKG2NM_006259.3 linkc.1736C>T p.Pro579Leu missense_variant 14/19 ENST00000264399.6 NP_006250.1 Q13237-1A0A140VJM3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PRKG2ENST00000264399.6 linkc.1736C>T p.Pro579Leu missense_variant 14/195 NM_006259.3 ENSP00000264399.1 Q13237-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000804
AC:
2
AN:
248774
Hom.:
0
AF XY:
0.00000743
AC XY:
1
AN XY:
134502
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000177
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000343
AC:
5
AN:
1458104
Hom.:
0
Cov.:
30
AF XY:
0.00000276
AC XY:
2
AN XY:
725400
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000187
Gnomad4 NFE exome
AF:
0.00000270
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000756

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMar 21, 2024The c.1736C>T (p.P579L) alteration is located in exon 13 (coding exon 13) of the PRKG2 gene. This alteration results from a C to T substitution at nucleotide position 1736, causing the proline (P) at amino acid position 579 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.95
BayesDel_addAF
Pathogenic
0.22
D
BayesDel_noAF
Uncertain
0.090
CADD
Pathogenic
33
DANN
Uncertain
1.0
DEOGEN2
Benign
0.13
T;T;T;.
Eigen
Pathogenic
0.78
Eigen_PC
Pathogenic
0.76
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.95
D;D;.;D
M_CAP
Benign
0.036
D
MetaRNN
Pathogenic
0.97
D;D;D;D
MetaSVM
Benign
-1.1
T
MutationAssessor
Uncertain
2.2
.;M;M;.
PrimateAI
Pathogenic
0.84
D
PROVEAN
Pathogenic
-9.9
D;D;D;.
REVEL
Uncertain
0.63
Sift
Pathogenic
0.0
D;D;D;.
Sift4G
Pathogenic
0.0
D;D;D;D
Polyphen
1.0
.;D;D;.
Vest4
0.97
MutPred
0.90
.;Loss of methylation at K578 (P = 0.0393);Loss of methylation at K578 (P = 0.0393);.;
MVP
0.57
MPC
1.5
ClinPred
1.0
D
GERP RS
5.8
Varity_R
0.89
gMVP
0.93

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.070
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs992380379; hg19: chr4-82056349; API