rs257376

Variant names:

• chr7-107159552-G-A
• rs257376
• NM_002736.3:c.1227G>A

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP7 BA1

The NM_002736.3(PRKAR2B):​c.1227G>A​(p.Thr409Thr) 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
• Publications: 32 publications found

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

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
PRKAR2B	NM_002736.3	c.1227G>A	p.Thr409Thr	synonymous_variant	Exon 11 of 11	ENST00000265717.5	NP_002727.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRKAR2B	ENST00000265717.5	c.1227G>A	p.Thr409Thr	synonymous_variant	Exon 11 of 11	1	NM_002736.3	ENSP00000265717.4

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

GnomAD2 exomes AF: 0.498 AC: 125280 AN: 251346 AF XY: 0.498

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 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

African (AFR) AF: 0.494 AC: 16543 AN: 33464

American (AMR) AF: 0.494 AC: 22104 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.581 AC: 15169 AN: 26120

East Asian (EAS) AF: 0.407 AC: 16162 AN: 39686

South Asian (SAS) AF: 0.382 AC: 32958 AN: 86222

European-Finnish (FIN) AF: 0.476 AC: 25409 AN: 53406

Middle Eastern (MID) AF: 0.449 AC: 2589 AN: 5766

European-Non Finnish (NFE) AF: 0.541 AC: 601012 AN: 1111454

Other (OTH) AF: 0.522 AC: 31497 AN: 60380

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

African (AFR) AF: 0.494 AC: 20494 AN: 41454

American (AMR) AF: 0.508 AC: 7765 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.566 AC: 1962 AN: 3466

East Asian (EAS) AF: 0.447 AC: 2313 AN: 5170

South Asian (SAS) AF: 0.366 AC: 1760 AN: 4810

European-Finnish (FIN) AF: 0.475 AC: 5013 AN: 10554

Middle Eastern (MID) AF: 0.497 AC: 145 AN: 292

European-Non Finnish (NFE) AF: 0.542 AC: 36819 AN: 67962

Other (OTH) AF: 0.493 AC: 1039 AN: 2108

Alfa AF: 0.532 Hom.: 43143

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
PhyloP100		0.58
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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