rs3730386

Positions:

• chr9-69013291-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

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 same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.28 (6354 hom., cov: 31)
  • Exomes 𝑓: 0.26 (51784 hom.)
• Consequence: PRKACG NM_002732.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.30

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]

ACMG classification

Verdict is Benign. Variant got -14 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_single_submitter, 1 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/exons	MANE	UniProt
PRKACG	NM_002732.4	c.802C>G	p.His268Asp	missense_variant	1/1	ENST00000377276.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKACG	ENST00000377276.5	c.802C>G	p.His268Asp	missense_variant	1/1		NM_002732.4	P1

Frequencies

GnomAD3 genomes AF: 0.282 AC: 42833 AN: 151828 Hom.: 6349 Cov.: 31

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

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.: 37 AF XY: 0.267 AC XY: 194491 AN XY: 727228

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.: 31 AF XY: 0.283 AC XY: 21028 AN XY: 74264

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:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 12, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	8.6
DANN	Benign	0.58
DEOGEN2	Benign	0.077	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.54	T
MetaRNN	Benign	0.028	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-2.1	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.37	T
PROVEAN	Benign	4.3	N
REVEL	Benign	0.069
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.059
MPC		0.44
ClinPred		0.0091	T
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

Other links and lift over

dbSNP: rs3730386; hg19: chr9-71628207; COSMIC: COSV55243645; COSMIC: COSV55243645;