rs56085217

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_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.

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

Publications

12 publications found

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 Gene-Disease associations (from GenCC):

cardioacrofacial dysplasia 1
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
Ellis-van Creveld syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
pigmented nodular adrenocortical disease, primary, 4
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

PRKACA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

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

BS2

High Homozygotes in GnomAd4 at 2 Unknown,AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002730.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PRKACA	NM_002730.4	MANE Select	c.137G>A	p.Arg46Gln	missense	Exon 3 of 10	NP_002721.1	P17612-1
PRKACA	NM_001304349.2		c.365G>A	p.Arg122Gln	missense	Exon 3 of 10	NP_001291278.1	A0A8V8TL59
PRKACA	NM_207518.3		c.113G>A	p.Arg38Gln	missense	Exon 3 of 10	NP_997401.1	P17612-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PRKACA	ENST00000308677.9	TSL:1 MANE Select	c.137G>A	p.Arg46Gln	missense	Exon 3 of 10	ENSP00000309591.3	P17612-1
PRKACA	ENST00000350356.7	TSL:2	c.365G>A	p.Arg122Gln	missense	Exon 3 of 10	ENSP00000513361.1	A0A8V8TL59
PRKACA	ENST00000589994.6	TSL:2	c.113G>A	p.Arg38Gln	missense	Exon 3 of 10	ENSP00000466651.1	P17612-2

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

GnomAD2 exomes

AF:

0.00198

AC:

498

AN:

251400

AF XY:

0.00194

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 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

African (AFR)

AF:

0.0000299

AC:

AN:

33480

American (AMR)

AF:

0.0000447

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.000209

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.0159

AC:

849

AN:

53418

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000419

AC:

466

AN:

1111986

Other (OTH)

AF:

0.000828

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

149

224

298

373

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00153

AC:

233

AN:

152300

Hom.:

Cov.:

AF XY:

0.00211

AC XY:

157

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.000144

AC:

AN:

41588

American (AMR)

AF:

0.0000654

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5152

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0165

AC:

175

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000720

AC:

AN:

68022

Other (OTH)

AF:

0.000946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000548

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 v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.44

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.32

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.25

Eigen

Benign

-0.38

Eigen_PC

Benign

-0.28

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.97

MetaRNN

Benign

0.0070

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.2

PhyloP100

6.2

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-1.7

REVEL

Benign

0.26

Sift

Benign

0.32

Sift4G

Benign

0.28

Polyphen

0.13

Vest4

0.84

MVP

0.75

MPC

1.2

ClinPred

0.031

GERP RS

3.9

PromoterAI

-0.018

Neutral

(source)

Varity_R

0.19

gMVP

0.75

Mutation Taster

=68/32

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over