Genetic Variant NM_002732.4:c.802C>G (chr9-69013291-G-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id 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

GnomAD3 exomes

AF:

0.268

AC:

67386

AN:

251366

Hom.:

9776

AF XY:

0.277

AC XY:

37697

AN XY:

135850

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 SAS exome

AF:

0.390

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

Gnomad4 AFR exome

AF:

0.373

Gnomad4 AMR exome

AF:

0.149

Gnomad4 ASJ exome

AF:

0.315

Gnomad4 EAS exome

AF:

0.274

Gnomad4 SAS exome

AF:

0.386

Gnomad4 FIN exome

AF:

0.220

Gnomad4 NFE exome

AF:

0.253

Gnomad4 OTH exome

AF:

0.275

GnomAD4 genome

AF:

0.282

AC:

42860

AN:

151946

Hom.:

6354

Cov.:

AF XY:

0.283

AC XY:

21028

AN XY:

74264

show subpopulations

Gnomad4 AFR

AF:

0.358

Gnomad4 AMR

AF:

0.206

Gnomad4 ASJ

AF:

0.311

Gnomad4 EAS

AF:

0.313

Gnomad4 SAS

AF:

0.393

Gnomad4 FIN

AF:

0.208

Gnomad4 NFE

AF:

0.253

Gnomad4 OTH

AF:

0.268

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

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

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

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

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over