7-107045103-G-A

Variant names:

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

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_002736.3(PRKAR2B):​c.196G>A​(p.Gly66Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000582 in 1,374,288 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000058 (0 hom.)
• Consequence: PRKAR2B NM_002736.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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 Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.27306566).
• BS2: High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000778 AC: 1 AN: 128456 Hom.: 0 AF XY: 0.0000142 AC XY: 1 AN XY: 70424

Gnomad AFR exome AF: 0.000171

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000582 AC: 8 AN: 1374288 Hom.: 0 Cov.: 34 AF XY: 0.00000444 AC XY: 3 AN XY: 676386

Gnomad4 AFR exome AF: 0.0000644

Gnomad4 AMR exome AF: 0.00

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: 0.00000560

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 22, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.196G>A (p.G66R) alteration is located in exon 1 (coding exon 1) of the PRKAR2B gene. This alteration results from a G to A substitution at nucleotide position 196, causing the glycine (G) at amino acid position 66 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	Benign	0.14
BayesDel_addAF	Uncertain	0.028	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.066
FATHMM_MKL	Uncertain	0.90	D
M_CAP	Pathogenic	0.63	D
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-0.70	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		0.39	B
Vest4		0.16
MutPred		0.30		Gain of MoRF binding (P = 0.0073);
MVP		0.77
MPC		1.1
ClinPred		0.37	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;