rs257376

Positions:

• chr7-107159552-G-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Moderate BP7 BA1

The NM_002736.3(PRKAR2B):​c.1227G>A​(p.Thr409=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.522 in 1,613,210 control chromosomes in the GnomAD database, including 221,514 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.51 (20158 hom., cov: 32)
  • Exomes 𝑓: 0.52 (201356 hom.)
• Consequence: PRKAR2B NM_002736.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.576

Genes affected

PRKAR2B (HGNC:9392): (protein kinase cAMP-dependent type II regulatory subunit beta) 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. This subunit has been shown to interact with and suppress the transcriptional activity of the cAMP responsive element binding protein 1 (CREB1) in activated T cells. Knockout studies in mice suggest that this subunit may play an important role in regulating energy balance and adiposity. The studies also suggest that this subunit may mediate the gene induction and cataleptic behavior induced by haloperidol. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP7: Synonymous conserved (PhyloP=0.576 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.537 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRKAR2B	NM_002736.3	c.1227G>A	p.Thr409=	synonymous_variant	11/11	ENST00000265717.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKAR2B	ENST00000265717.5	c.1227G>A	p.Thr409=	synonymous_variant	11/11	1	NM_002736.3	P1

Frequencies

GnomAD3 genomes AF: 0.512 AC: 77798 AN: 151888 Hom.: 20138 Cov.: 32

Gnomad AFR AF: 0.494

Gnomad AMI AF: 0.621

Gnomad AMR AF: 0.508

Gnomad ASJ AF: 0.566

Gnomad EAS AF: 0.447

Gnomad SAS AF: 0.365

Gnomad FIN AF: 0.475

Gnomad MID AF: 0.494

Gnomad NFE AF: 0.542

Gnomad OTH AF: 0.493

GnomAD3 exomes AF: 0.498 AC: 125280 AN: 251346 Hom.: 31661 AF XY: 0.498 AC XY: 67597 AN XY: 135846

Gnomad AFR exome AF: 0.501

Gnomad AMR exome AF: 0.489

Gnomad ASJ exome AF: 0.575

Gnomad EAS exome AF: 0.449

Gnomad SAS exome AF: 0.384

Gnomad FIN exome AF: 0.470

Gnomad NFE exome AF: 0.538

Gnomad OTH exome AF: 0.515

GnomAD4 exome AF: 0.522 AC: 763443 AN: 1461204 Hom.: 201356 Cov.: 46 AF XY: 0.519 AC XY: 377550 AN XY: 726956

Gnomad4 AFR exome AF: 0.494

Gnomad4 AMR exome AF: 0.494

Gnomad4 ASJ exome AF: 0.581

Gnomad4 EAS exome AF: 0.407

Gnomad4 SAS exome AF: 0.382

Gnomad4 FIN exome AF: 0.476

Gnomad4 NFE exome AF: 0.541

Gnomad4 OTH exome AF: 0.522

GnomAD4 genome AF: 0.512 AC: 77874 AN: 152006 Hom.: 20158 Cov.: 32 AF XY: 0.506 AC XY: 37587 AN XY: 74296

Gnomad4 AFR AF: 0.494

Gnomad4 AMR AF: 0.508

Gnomad4 ASJ AF: 0.566

Gnomad4 EAS AF: 0.447

Gnomad4 SAS AF: 0.366

Gnomad4 FIN AF: 0.475

Gnomad4 NFE AF: 0.542

Gnomad4 OTH AF: 0.493

Alfa AF: 0.536 Hom.: 33649

Bravo AF: 0.522

Asia WGS AF: 0.449 AC: 1562 AN: 3478

EpiCase AF: 0.549

EpiControl AF: 0.546

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	6.6
DANN	Benign	0.63

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: rs257376; hg19: chr7-106799997; COSMIC: COSV55923337;