chr3-48790617-G-C

Position:

• chr3-48790617-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_004157.4(PRKAR2A):​c.362C>G​(p.Pro121Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: PRKAR2A NM_004157.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.95

Genes affected

PRKAR2A (HGNC:9391): (protein kinase cAMP-dependent type II regulatory subunit alpha) cAMP is a signaling molecule important for a variety of cellular functions. cAMP exerts its effects by activating the cAMP-dependent protein kinase, which transduces the signal through phosphorylation of different target proteins. The inactive kinase holoenzyme is a tetramer composed of two regulatory and two catalytic subunits. cAMP causes the dissociation of the inactive holoenzyme into a dimer of regulatory subunits bound to four cAMP and two free monomeric catalytic subunits. Four different regulatory subunits and three catalytic subunits have been identified in humans. The protein encoded by this gene is one of the regulatory subunits. This subunit can be phosphorylated by the activated catalytic subunit. It may interact with various A-kinase anchoring proteins and determine the subcellular localization of cAMP-dependent protein kinase. This subunit has been shown to regulate protein transport from endosomes to the Golgi apparatus and further to the endoplasmic reticulum (ER). [provided by RefSeq, Jul 2008]

PRKAR2A (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.754

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRKAR2A	NM_004157.4	c.362C>G	p.Pro121Arg	missense_variant	4/11	ENST00000265563.13	NP_004148.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRKAR2A	ENST00000265563.13	c.362C>G	p.Pro121Arg	missense_variant	4/11	1	NM_004157.4	ENSP00000265563.8

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 11, 2024

The c.362C>G (p.P121R) alteration is located in exon 4 (coding exon 4) of the PRKAR2A gene. This alteration results from a C to G substitution at nucleotide position 362, causing the proline (P) at amino acid position 121 to be replaced by an arginine (R). 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	Uncertain	0.41
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.64	D;D;.;.
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.85	.;D;D;T
M_CAP	Benign	0.028	D
MetaRNN	Pathogenic	0.75	D;D;D;D
MetaSVM	Benign	-0.47	T
MutationAssessor	Uncertain	2.8	M;M;M;.
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-8.3	D;D;D;D
REVEL	Uncertain	0.53
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;.
Polyphen		1.0	D;D;.;.
Vest4		0.83
MutPred		0.33		Loss of catalytic residue at P121 (P = 0.0222);Loss of catalytic residue at P121 (P = 0.0222);Loss of catalytic residue at P121 (P = 0.0222);.;
MVP		0.73
MPC		0.46
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.77
gMVP		0.49

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: chr3-48828050;