chr7-107070321-G-A

Position:

• chr7-107070321-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_002736.3(PRKAR2B):​c.343+5G>A variant causes a splice region, intron change. The variant allele was found at a frequency of 0.00354 in 1,599,534 control chromosomes in the GnomAD database, including 152 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (93 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (59 hom.)
• Consequence: PRKAR2B NM_002736.3 splice_region, intron
• Scores: Splicing: ADA: 0.6660
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.96

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]

PRKAR2B (HGNC:):

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.25).
• BP6: Variant 7-107070321-G-A is Benign according to our data. Variant chr7-107070321-G-A is described in ClinVar as [Benign]. Clinvar id is 780702.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0596 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRKAR2B	NM_002736.3	c.343+5G>A		splice_region_variant, intron_variant		ENST00000265717.5	NP_002727.2
PRKAR2B-AS1	XR_007060469.1	n.145-1453C>T		intron_variant
PRKAR2B-AS1	XR_007060470.1	n.313-1453C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRKAR2B	ENST00000265717.5	c.343+5G>A		splice_region_variant, intron_variant		1	NM_002736.3	ENSP00000265717.4

Frequencies

GnomAD3 genomes AF: 0.0183 AC: 2783 AN: 152142 Hom.: 91 Cov.: 32

Gnomad AFR AF: 0.0616

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0109

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000588

Gnomad OTH AF: 0.00955

GnomAD3 exomes AF: 0.00529 AC: 1318 AN: 249174 Hom.: 43 AF XY: 0.00396 AC XY: 533 AN XY: 134718

Gnomad AFR exome AF: 0.0649

Gnomad AMR exome AF: 0.00470

Gnomad ASJ exome AF: 0.00199

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000996

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000548

Gnomad OTH exome AF: 0.00394

GnomAD4 exome AF: 0.00198 AC: 2872 AN: 1447274 Hom.: 59 Cov.: 28 AF XY: 0.00180 AC XY: 1294 AN XY: 720706

Gnomad4 AFR exome AF: 0.0568

Gnomad4 AMR exome AF: 0.00515

Gnomad4 ASJ exome AF: 0.00150

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000140

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000382

Gnomad4 OTH exome AF: 0.00462

GnomAD4 genome AF: 0.0183 AC: 2788 AN: 152260 Hom.: 93 Cov.: 32 AF XY: 0.0180 AC XY: 1341 AN XY: 74440

Gnomad4 AFR AF: 0.0616

Gnomad4 AMR AF: 0.0109

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000573

Gnomad4 OTH AF: 0.00945

Alfa AF: 0.00180 Hom.: 6

Bravo AF: 0.0209

Asia WGS AF: 0.00520 AC: 18 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	24
DANN	Benign	0.95

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.67
dbscSNV1_RF	Benign	0.53
SpliceAI score (max)		0.040		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: rs3729869; hg19: chr7-106710766;