4-81144316-G-A

Position:

• chr4-81144316-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001282480.1(PRKG2):​c.-92C>T variant causes a 5 prime UTR premature start codon gain change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PRKG2 NM_001282480.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.91

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRKG2	NM_006259.3	c.1169C>T	p.Thr390Ile	missense_variant	10/19	ENST00000264399.6	NP_006250.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRKG2	ENST00000264399.6	c.1169C>T	p.Thr390Ile	missense_variant	10/19	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

Sep 11, 2024

The c.1169C>T (p.T390I) alteration is located in exon 9 (coding exon 9) of the PRKG2 gene. This alteration results from a C to T substitution at nucleotide position 1169, causing the threonine (T) at amino acid position 390 to be replaced by an isoleucine (I). 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	0.69
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T;T;.
Eigen	Benign	-0.14
Eigen_PC	Benign	0.099
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.86	D;.;D
M_CAP	Uncertain	0.088	D
MetaRNN	Uncertain	0.50	T;T;T
MetaSVM	Benign	-0.28	T
MutationAssessor	Benign	-1.1	N;N;N
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	1.4	N;N;.
REVEL	Uncertain	0.50
Sift	Uncertain	0.014	D;D;.
Sift4G	Uncertain	0.030	D;D;T
Polyphen		0.036	B;B;.
Vest4		0.65
MutPred		0.50		Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);
MVP		0.92
MPC		1.3
ClinPred		0.97	D
GERP RS		5.3
Varity_R		0.52
gMVP		0.80

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: chr4-82065470;