rs56085217

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP2BP4_StrongBS2

The NM_002730.4(PRKACA):c.137G>A(p.Arg46Gln) variant causes a missense change. The variant allele was found at a frequency of 0.001 in 1,614,152 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.0015 ( 2 hom., cov: 32)

Exomes 𝑓: 0.00095 ( 11 hom. )

Consequence

PRKACA
NM_002730.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.17

Variant links:

Genes affected

PRKACA (HGNC:9380): (protein kinase cAMP-activated catalytic subunit alpha) This gene encodes one of the catalytic subunits of protein kinase A, which exists as a tetrameric holoenzyme with two regulatory subunits and two catalytic subunits, in its inactive form. 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. cAMP-dependent phosphorylation of proteins by protein kinase A is important to many cellular processes, including differentiation, proliferation, and apoptosis. Constitutive activation of this gene caused either by somatic mutations, or genomic duplications of regions that include this gene, have been associated with hyperplasias and adenomas of the adrenal cortex and are linked to corticotropin-independent Cushing's syndrome. Alternative splicing results in multiple transcript variants encoding different isoforms. Tissue-specific isoforms that differ at the N-terminus have been described, and these isoforms may differ in the post-translational modifications that occur at the N-terminus of some isoforms. [provided by RefSeq, Jan 2015]

PRKACA links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

PP2

Missense variant where missense usually causes diseases, PRKACA

BP4

Computational evidence support a benign effect (MetaRNN=0.007042855).

BS2

High AC in GnomAd at 233 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
PRKACA	NM_002730.4 linkuse as main transcript	c.137G>A	p.Arg46Gln	missense_variant	3/10	ENST00000308677.9
PRKACA	NM_001304349.2 linkuse as main transcript	c.365G>A	p.Arg122Gln	missense_variant	3/10
PRKACA	NM_207518.3 linkuse as main transcript	c.113G>A	p.Arg38Gln	missense_variant	3/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKACA	ENST00000308677.9 linkuse as main transcript	c.137G>A	p.Arg46Gln	missense_variant	3/10	1	NM_002730.4	P1	P17612-1

Frequencies

GnomAD3 genomes

AF:

0.00153

AC:

233

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0165

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000720

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.00198

AC:

498

AN:

251400

Hom.:

AF XY:

0.00194

AC XY:

263

AN XY:

135902

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.0167

Gnomad NFE exome

AF:

0.00102

Gnomad OTH exome

AF:

0.00179

GnomAD4 exome

AF:

0.000949

AC:

1387

AN:

1461852

Hom.:

Cov.:

AF XY:

0.000902

AC XY:

656

AN XY:

727228

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000209

Gnomad4 FIN exome

AF:

0.0159

Gnomad4 NFE exome

AF:

0.000419

Gnomad4 OTH exome

AF:

0.000828

GnomAD4 genome

AF:

0.00153

AC:

233

AN:

152300

Hom.:

Cov.:

AF XY:

0.00211

AC XY:

157

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.000144

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0165

Gnomad4 NFE

AF:

0.000720

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.000481

Hom.:

Bravo

AF:

0.000280

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00184

AC:

223

EpiCase

AF:

0.000273

EpiControl

AF:

0.000474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.44

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.32

Cadd

Pathogenic

Dann

Uncertain

0.99

DEOGEN2

Benign

0.25

T;.;.

Eigen

Benign

-0.38

Eigen_PC

Benign

-0.28

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.97

D;D;D

MetaRNN

Benign

0.0070

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.2

L;.;.

MutationTaster

Benign

1.0

D;N;N;N

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-1.7

N;.;.

REVEL

Benign

0.26

Sift

Benign

0.32

T;.;.

Sift4G

Benign

0.28

T;T;T

Polyphen

0.13

B;B;.

Vest4

0.84

MVP

0.75

MPC

1.2

ClinPred

0.031

GERP RS

3.9

Varity_R

0.19

gMVP

0.75

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over