3-48794029-G-A

Position:

• chr3-48794029-G-A

Variant summary

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

The NM_004157.4(PRKAR2A):​c.319C>T​(p.Pro107Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000688 in 1,453,364 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: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: PRKAR2A NM_004157.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.72

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]

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, 0.767

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRKAR2A	NM_004157.4	c.319C>T	p.Pro107Ser	missense_variant	3/11	ENST00000265563.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKAR2A	ENST00000265563.13	c.319C>T	p.Pro107Ser	missense_variant	3/11	1	NM_004157.4	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1453364 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 723486

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

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

May 06, 2022

The c.319C>T (p.P107S) alteration is located in exon 3 (coding exon 3) of the PRKAR2A gene. This alteration results from a C to T substitution at nucleotide position 319, causing the proline (P) at amino acid position 107 to be replaced by a serine (S). 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	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.68	D;D;.;.
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.96	.;D;D;D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.77	D;D;D;D
MetaSVM	Uncertain	0.44	D
MutationAssessor	Uncertain	2.8	M;M;M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-7.6	D;D;D;D
REVEL	Uncertain	0.62
Sift	Uncertain	0.014	D;D;D;D
Sift4G	Uncertain	0.043	D;D;D;.
Polyphen		0.88	P;P;.;.
Vest4		0.50
MutPred		0.30		Gain of phosphorylation at P107 (P = 0.0213);Gain of phosphorylation at P107 (P = 0.0213);Gain of phosphorylation at P107 (P = 0.0213);.;
MVP		0.77
MPC		1.2
ClinPred		1.0	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.55
gMVP		0.52

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

LitVar

Other links and lift over

dbSNP: rs746644588; hg19: chr3-48831462;