4-81169663-C-T

Position:

• chr4-81169663-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_006259.3(PRKG2):​c.848G>A​(p.Ser283Asn) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PRKG2 NM_006259.3 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.35

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 3 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRKG2	NM_006259.3	c.848G>A	p.Ser283Asn	missense_variant, splice_region_variant	5/19	ENST00000264399.6	NP_006250.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRKG2	ENST00000264399.6	c.848G>A	p.Ser283Asn	missense_variant, splice_region_variant	5/19	5	NM_006259.3	ENSP00000264399.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Acromesomelic dysplasia 4 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

Dec 19, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.65	D;D;.
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;.;D
M_CAP	Benign	0.052	D
MetaRNN	Uncertain	0.49	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.4	M;M;M
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-2.4	N;N;.
REVEL	Benign	0.20
Sift	Uncertain	0.0080	D;D;.
Sift4G	Uncertain	0.020	D;D;D
Polyphen		0.39	B;B;.
Vest4		0.59
MutPred		0.43		Loss of loop (P = 0.0804);Loss of loop (P = 0.0804);Loss of loop (P = 0.0804);
MVP		0.59
MPC		1.4
ClinPred		0.97	D
GERP RS		6.1
Varity_R		0.28
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.71		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.71		Position offset: 0

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: chr4-82090817;