1-84182209-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM1 BP4_Moderate BS2

The NM_182948.4(PRKACB):c.259G>A(p.Gly87Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000205 in 1,561,290 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000021 (1 hom.)
• Consequence: PRKACB NM_182948.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.99

Genes affected

PRKACB (HGNC:9381): (protein kinase cAMP-activated catalytic subunit beta) The protein encoded by this gene is a member of the serine/threonine protein kinase family. The encoded protein is a catalytic subunit of cAMP (cyclic AMP)-dependent protein kinase, which mediates signalling though cAMP. cAMP signaling is important to a number of processes, including cell proliferaton and differentiation. Multiple alternatively spliced transcript variants encoding distinct isoforms have been observed. [provided by RefSeq, Jul 2014]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM1: In a domain Protein kinase (size 254) in uniprot entity KAPCB_HUMAN there are 9 pathogenic changes around while only 1 benign (90%) in NM_182948.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.121797115).
• BS2: High AC in GnomAdExome at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRKACB	NM_182948.4	c.259G>A	p.Gly87Arg	missense_variant	3/10	ENST00000370685.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKACB	ENST00000370685.7	c.259G>A	p.Gly87Arg	missense_variant	3/10	1	NM_182948.4

Frequencies

GnomAD3 genomes AF: 0.0000198 AC: 3 AN: 151650 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000132

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000475 AC: 11 AN: 231662 Hom.: 1 AF XY: 0.0000478 AC XY: 6 AN XY: 125618

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000671

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000374

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000746

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000206 AC: 29 AN: 1409640 Hom.: 1 Cov.: 29 AF XY: 0.0000171 AC XY: 12 AN XY: 701084

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000125

Gnomad4 ASJ exome AF: 0.0000401

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000387

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000157

Gnomad4 OTH exome AF: 0.0000515

GnomAD4 genome AF: 0.0000198 AC: 3 AN: 151650 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74004

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000132

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000451 Hom.: 0

Bravo AF: 0.0000340

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 22, 2023

The c.259G>A (p.G87R) alteration is located in exon 3 (coding exon 3) of the PRKACB gene. This alteration results from a G to A substitution at nucleotide position 259, causing the glycine (G) at amino acid position 87 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	0.22
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.41
Cadd	Benign	23
Dann	Uncertain	0.98
DEOGEN2	Benign	0.23	T;.;.;.;.;.;.;.;T;.;.;.;.;.;.;.;T
Eigen	Benign	-0.0080
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.0099	T
MetaRNN	Benign	0.12	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L;L;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.73	N;N;N;N;N;N;.;N;.;N;N;N;N;N;.;N;.
REVEL	Benign	0.10
Sift	Benign	0.26	T;T;T;T;T;T;.;T;.;T;T;T;T;T;.;T;.
Sift4G	Benign	0.27	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.50	P;B;B;.;.;.;B;B;.;.;.;B;.;.;B;.;.
Vest4		0.44
MutPred		0.21		Loss of catalytic residue at A39 (P = 0.0492);Loss of catalytic residue at A39 (P = 0.0492);.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;
MVP		0.38
MPC		1.0
ClinPred		0.15	T
GERP RS		5.5
Varity_R		0.097
gMVP		0.55

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs148797911; hg19: chr1-84647892; COSMIC: COSV100853982;