4-81174889-T-C

Position:

• chr4-81174889-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_006259.3(PRKG2):​c.532A>G​(p.Lys178Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PRKG2 NM_006259.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.64

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]

PRKG2-AS1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PRKG2. . Gene score misZ 2.9899 (greater than the threshold 3.09). Trascript score misZ 3.189 (greater than threshold 3.09). GenCC has associacion of gene with acromesomelic dysplasia 4.
• BP4: Computational evidence support a benign effect (MetaRNN=0.2217826).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRKG2	NM_006259.3	c.532A>G	p.Lys178Glu	missense_variant	3/19	ENST00000264399.6	NP_006250.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRKG2	ENST00000264399.6	c.532A>G	p.Lys178Glu	missense_variant	3/19	5	NM_006259.3	ENSP00000264399.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 03, 2024

The c.532A>G (p.K178E) alteration is located in exon 2 (coding exon 2) of the PRKG2 gene. This alteration results from a A to G substitution at nucleotide position 532, causing the lysine (K) at amino acid position 178 to be replaced by a glutamic acid (E). 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	Benign	0.18
BayesDel_addAF	Uncertain	0.034	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T;T;.
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.054
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.85	D;.;D
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.22	T;T;T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	0.90	L;L;L
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.4	N;N;.
REVEL	Benign	0.28
Sift	Benign	0.26	T;T;.
Sift4G	Benign	0.58	T;T;T
Polyphen		0.0010	B;B;.
Vest4		0.32
MutPred		0.45		Loss of methylation at K178 (P = 0.0145);Loss of methylation at K178 (P = 0.0145);Loss of methylation at K178 (P = 0.0145);
MVP		0.92
MPC		0.87
ClinPred		0.61	D
GERP RS		6.0
Varity_R		0.50
gMVP		0.68

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-82096043;