7-550592-T-C

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_001164760.2(PRKAR1B):c.984A>G(p.Ala328=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0113 in 1,579,800 control chromosomes in the GnomAD database, including 885 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.022 (124 hom., cov: 32)
  • Exomes 𝑓: 0.010 (761 hom.)
• Consequence: PRKAR1B NM_001164760.2 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:3
• Conservation: PhyloP100: -3.64

Genes affected

PRKAR1B (HGNC:9390): (protein kinase cAMP-dependent type I regulatory subunit beta) The protein encoded by this gene is a regulatory subunit of cyclic AMP-dependent protein kinase A (PKA), which is involved in the signaling pathway of the second messenger cAMP. Two regulatory and two catalytic subunits form the PKA holoenzyme, disbands after cAMP binding. The holoenzyme is involved in many cellular events, including ion transport, metabolism, and transcription. Several transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Aug 2015]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 7-550592-T-C is Benign according to our data. Variant chr7-550592-T-C is described in ClinVar as [Benign]. Clinvar id is 1210095.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-550592-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-3.64 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.143 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRKAR1B	NM_001164760.2	c.984A>G	p.Ala328=	synonymous_variant	11/11	ENST00000537384.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKAR1B	ENST00000537384.6	c.984A>G	p.Ala328=	synonymous_variant	11/11	5	NM_001164760.2	P1

Frequencies

GnomAD3 genomes AF: 0.0221 AC: 3358 AN: 151804 Hom.: 125 Cov.: 32

Gnomad AFR AF: 0.0483

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.00767

Gnomad ASJ AF: 0.00663

Gnomad EAS AF: 0.152

Gnomad SAS AF: 0.0174

Gnomad FIN AF: 0.00123

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00424

Gnomad OTH AF: 0.0215

GnomAD3 exomes AF: 0.0214 AC: 4460 AN: 208320 Hom.: 251 AF XY: 0.0201 AC XY: 2290 AN XY: 114066

Gnomad AFR exome AF: 0.0481

Gnomad AMR exome AF: 0.00426

Gnomad ASJ exome AF: 0.00342

Gnomad EAS exome AF: 0.169

Gnomad SAS exome AF: 0.0161

Gnomad FIN exome AF: 0.00138

Gnomad NFE exome AF: 0.00399

Gnomad OTH exome AF: 0.0150

GnomAD4 exome AF: 0.0101 AC: 14436 AN: 1427878 Hom.: 761 Cov.: 32 AF XY: 0.0102 AC XY: 7258 AN XY: 708444

Gnomad4 AFR exome AF: 0.0510

Gnomad4 AMR exome AF: 0.00454

Gnomad4 ASJ exome AF: 0.00372

Gnomad4 EAS exome AF: 0.179

Gnomad4 SAS exome AF: 0.0144

Gnomad4 FIN exome AF: 0.00154

Gnomad4 NFE exome AF: 0.00290

Gnomad4 OTH exome AF: 0.0162

GnomAD4 genome AF: 0.0222 AC: 3368 AN: 151922 Hom.: 124 Cov.: 32 AF XY: 0.0230 AC XY: 1712 AN XY: 74280

Gnomad4 AFR AF: 0.0486

Gnomad4 AMR AF: 0.00759

Gnomad4 ASJ AF: 0.00663

Gnomad4 EAS AF: 0.152

Gnomad4 SAS AF: 0.0168

Gnomad4 FIN AF: 0.00123

Gnomad4 NFE AF: 0.00424

Gnomad4 OTH AF: 0.0208

Alfa AF: 0.00638 Hom.: 3

Bravo AF: 0.0241

Asia WGS AF: 0.0760 AC: 264 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

PRKAR1B-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 02, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
Cadd	Benign	0.086
Dann	Benign	0.45

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: rs28626752; hg19: chr7-590229; COSMIC: COSV64319192;