rs56085217

Positions:

• chr19-14106860-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP2 BP4_Strong BS2

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.17

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]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PRKACA. . Gene score misZ 2.9714 (greater than the threshold 3.09). Trascript score misZ 3.8384 (greater than threshold 3.09). GenCC has associacion of gene with cardioacrofacial dysplasia 1, pigmented nodular adrenocortical disease, primary, 4.
• BP4: Computational evidence support a benign effect (MetaRNN=0.007042855).
• BS2: High AC in GnomAd4 at 233 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRKACA	NM_002730.4	c.137G>A	p.Arg46Gln	missense_variant	3/10	ENST00000308677.9	NP_002721.1
PRKACA	NM_001304349.2	c.365G>A	p.Arg122Gln	missense_variant	3/10		NP_001291278.1
PRKACA	NM_207518.3	c.113G>A	p.Arg38Gln	missense_variant	3/10		NP_997401.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRKACA	ENST00000308677.9	c.137G>A	p.Arg46Gln	missense_variant	3/10	1	NM_002730.4	ENSP00000309591	P1

Frequencies

GnomAD3 genomes AF: 0.00153 AC: 233 AN: 152182 Hom.: 2 Cov.: 32

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.: 4 AF XY: 0.00194 AC XY: 263 AN XY: 135902

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.: 11 Cov.: 31 AF XY: 0.000902 AC XY: 656 AN XY: 727228

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.: 2 Cov.: 32 AF XY: 0.00211 AC XY: 157 AN XY: 74464

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.: 0

Bravo AF: 0.000280

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

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	T
BayesDel_noAF	Benign	-0.32
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.25	T;.;.
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.28
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.97	D;D;D
MetaRNN	Benign	0.0070	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L;.;.
MutationTaster	Benign	1.0	D;N;N;N
PrimateAI	Uncertain	0.58	T
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	T
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

Other links and lift over

dbSNP: rs56085217; hg19: chr19-14217672; COSMIC: COSV58067965;