NM_002736.3:c.196G>C

Variant names:

• chr7-107045103-G-C
• rs1285830362
• NM_002736.3:c.196G>C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002736.3(PRKAR2B):​c.196G>C​(p.Gly66Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000728 in 1,374,288 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 32)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: PRKAR2B NM_002736.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.09

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2663207).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKAR2B	NM_002736.3	c.196G>C	p.Gly66Arg	missense_variant	Exon 1 of 11	ENST00000265717.5	NP_002727.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRKAR2B	ENST00000265717.5	c.196G>C	p.Gly66Arg	missense_variant	Exon 1 of 11	1	NM_002736.3	ENSP00000265717.4
PRKAR2B	ENST00000706580.1	n.194G>C		non_coding_transcript_exon_variant	Exon 1 of 8
PRKAR2B	ENST00000706581.1	c.-45G>C		upstream_gene_variant				ENSP00000516463.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000156 AC: 2 AN: 128456 Hom.: 0 AF XY: 0.0000142 AC XY: 1 AN XY: 70424

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000963

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000149

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.28e-7 AC: 1 AN: 1374288 Hom.: 0 Cov.: 34 AF XY: 0.00000148 AC XY: 1 AN XY: 676386

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000283

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.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.029	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.097
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Pathogenic	0.61	D
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	0.0	N
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-0.28	N
REVEL	Uncertain	0.35
Sift	Benign	0.41	T
Sift4G	Benign	0.63	T
Polyphen		0.23	B
Vest4		0.16
MutPred		0.30		Gain of MoRF binding (P = 0.0073);
MVP		0.77
MPC		1.1
ClinPred		0.14	T
GERP RS		4.1
Varity_R		0.16
gMVP		0.41

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: rs1285830362; hg19: chr7-106685548;