dbSNP rs3730386: PRKACG:p.His268Asp (chr9-69013291-G-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002732.4(PRKACG):c.802C>G(p.His268Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.264 in 1,613,806 control chromosomes in the GnomAD database, including 58,138 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.28 ( 6354 hom., cov: 31)

Exomes 𝑓: 0.26 ( 51784 hom. )

Consequence

PRKACG
NM_002732.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 2.30

Publications

35 publications found

Variant links:

Genes affected

PRKACG (HGNC:9382): (protein kinase cAMP-activated catalytic subunit gamma) Cyclic AMP-dependent protein kinase (PKA) consists of two catalytic subunits and a regulatory subunit dimer. This gene encodes the gamma form of its catalytic subunit. The gene is intronless and is thought to be a retrotransposon derived from the gene for the alpha form of the PKA catalytic subunit. [provided by RefSeq, Jul 2008]

PRKACG Gene-Disease associations (from GenCC):

platelet-type bleeding disorder 19
Inheritance: AR Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

PRKACG links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.028394818).

BP6

Variant 9-69013291-G-C is Benign according to our data. Variant chr9-69013291-G-C is described in ClinVar as Benign. ClinVar VariationId is 1268030.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.378 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKACG	NM_002732.4 link	c.802C>G	p.His268Asp	missense_variant	Exon 1 of 1	ENST00000377276.5	NP_002723.2	P22612

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRKACG	ENST00000377276.5 link	c.802C>G	p.His268Asp	missense_variant	Exon 1 of 1	6	NM_002732.4	ENSP00000366488.2		P22612

Frequencies

GnomAD3 genomes

AF:

0.282

AC:

42833

AN:

151828

Hom.:

6349

Cov.:

show subpopulations

Gnomad AFR

AF:

0.358

Gnomad AMI

AF:

0.240

Gnomad AMR

AF:

0.206

Gnomad ASJ

AF:

0.311

Gnomad EAS

AF:

0.313

Gnomad SAS

AF:

0.392

Gnomad FIN

AF:

0.208

Gnomad MID

AF:

0.342

Gnomad NFE

AF:

0.253

Gnomad OTH

AF:

0.272

GnomAD2 exomes

AF:

0.268

AC:

67386

AN:

251366

AF XY:

0.277

show subpopulations

Gnomad AFR exome

AF:

0.369

Gnomad AMR exome

AF:

0.139

Gnomad ASJ exome

AF:

0.312

Gnomad EAS exome

AF:

0.319

Gnomad FIN exome

AF:

0.221

Gnomad NFE exome

AF:

0.257

Gnomad OTH exome

AF:

0.272

GnomAD4 exome

AF:

0.262

AC:

382725

AN:

1461860

Hom.:

51784

Cov.:

AF XY:

0.267

AC XY:

194491

AN XY:

727228

show subpopulations

African (AFR)

AF:

0.373

AC:

12486

AN:

33480

American (AMR)

AF:

0.149

AC:

6667

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.315

AC:

8220

AN:

26136

East Asian (EAS)

AF:

0.274

AC:

10865

AN:

39700

South Asian (SAS)

AF:

0.386

AC:

33256

AN:

86256

European-Finnish (FIN)

AF:

0.220

AC:

11735

AN:

53408

Middle Eastern (MID)

AF:

0.330

AC:

1903

AN:

5768

European-Non Finnish (NFE)

AF:

0.253

AC:

280977

AN:

1111994

Other (OTH)

AF:

0.275

AC:

16616

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

18703

37407

56110

74814

93517

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9660

19320

28980

38640

48300

<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:

0.282

AC:

42860

AN:

151946

Hom.:

6354

Cov.:

AF XY:

0.283

AC XY:

21028

AN XY:

74264

show subpopulations

African (AFR)

AF:

0.358

AC:

14848

AN:

41432

American (AMR)

AF:

0.206

AC:

3145

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.311

AC:

1079

AN:

3468

East Asian (EAS)

AF:

0.313

AC:

1606

AN:

5124

South Asian (SAS)

AF:

0.393

AC:

1885

AN:

4800

European-Finnish (FIN)

AF:

0.208

AC:

2203

AN:

10600

Middle Eastern (MID)

AF:

0.344

AC:

101

AN:

294

European-Non Finnish (NFE)

AF:

0.253

AC:

17211

AN:

67948

Other (OTH)

AF:

0.268

AC:

564

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1532

3063

4595

6126

7658

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

444

888

1332

1776

2220

<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:

0.267

Hom.:

1911

Bravo

AF:

0.283

TwinsUK

AF:

0.251

AC:

932

ALSPAC

AF:

0.241

AC:

928

ESP6500AA

AF:

0.362

AC:

1596

ESP6500EA

AF:

0.256

AC:

2203

ExAC

AF:

0.275

AC:

33401

Asia WGS

AF:

0.300

AC:

1045

AN:

3478

EpiCase

AF:

0.267

EpiControl

AF:

0.273

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Nov 12, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.67

CADD

Benign

8.6

(source)

DANN

Benign

0.58

DEOGEN2

Benign

0.077

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.013

LIST_S2

Benign

0.54

MetaRNN

Benign

0.028

MetaSVM

Benign

-0.93

MutationAssessor

Benign

-2.1

PhyloP100

2.3

PrimateAI

Benign

0.37

PROVEAN

Benign

4.3

REVEL

Benign

0.069

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.059

MPC

0.44

ClinPred

0.0091

GERP RS

1.6

Varity_R

0.057

gMVP

0.56

Mutation Taster

=95/5

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over