rs56105247

Positions:

• chr19-14107354-G-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_002730.4(PRKACA):​c.102C>T​(p.Pro34Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00339 in 1,613,934 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0020 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0035 (17 hom.)
• Consequence: PRKACA NM_002730.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0110

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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 19-14107354-G-A is Benign according to our data. Variant chr19-14107354-G-A is described in ClinVar as [Benign]. Clinvar id is 708471.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.011 with no splicing effect.
• BS2: High AC in GnomAd4 at 309 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRKACA	NM_002730.4	c.102C>T	p.Pro34Pro	synonymous_variant	2/10	ENST00000308677.9	NP_002721.1
PRKACA	NM_001304349.2	c.330C>T	p.Pro110Pro	synonymous_variant	2/10		NP_001291278.1
PRKACA	NM_207518.3	c.78C>T	p.Pro26Pro	synonymous_variant	2/10		NP_997401.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRKACA	ENST00000308677.9	c.102C>T	p.Pro34Pro	synonymous_variant	2/10	1	NM_002730.4	ENSP00000309591.3

Frequencies

GnomAD3 genomes AF: 0.00203 AC: 309 AN: 152238 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000893

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000413

Gnomad FIN AF: 0.000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00351

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00238 AC: 599 AN: 251346 Hom.: 1 AF XY: 0.00237 AC XY: 322 AN XY: 135870

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.00127

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000653

Gnomad FIN exome AF: 0.00129

Gnomad NFE exome AF: 0.00418

Gnomad OTH exome AF: 0.00342

GnomAD4 exome AF: 0.00354 AC: 5169 AN: 1461578 Hom.: 17 Cov.: 31 AF XY: 0.00346 AC XY: 2516 AN XY: 727124

Gnomad4 AFR exome AF: 0.000448

Gnomad4 AMR exome AF: 0.00134

Gnomad4 ASJ exome AF: 0.000191

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000661

Gnomad4 FIN exome AF: 0.00202

Gnomad4 NFE exome AF: 0.00427

Gnomad4 OTH exome AF: 0.00296

GnomAD4 genome AF: 0.00203 AC: 309 AN: 152356 Hom.: 1 Cov.: 33 AF XY: 0.00184 AC XY: 137 AN XY: 74502

Gnomad4 AFR AF: 0.000890

Gnomad4 AMR AF: 0.000784

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.000941

Gnomad4 NFE AF: 0.00351

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00305 Hom.: 1

Bravo AF: 0.00217

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00376

EpiControl AF: 0.00326

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

Labcorp Genetics (formerly Invitae), Labcorp

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	11
DANN	Benign	0.60
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs56105247; hg19: chr19-14218166;