19-14100864-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Moderate BP6_Moderate BP7 BS1 BS2

The NM_002730.4(PRKACA):c.381G>A(p.Gly127=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000787 in 1,614,174 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00098 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00077 (12 hom.)
• Consequence: PRKACA NM_002730.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.303

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 19-14100864-C-T is Benign according to our data. Variant chr19-14100864-C-T is described in ClinVar as [Benign]. Clinvar id is 731258.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.303 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000978 (149/152346) while in subpopulation EAS AF= 0.0227 (118/5188). AF 95% confidence interval is 0.0194. There are 4 homozygotes in gnomad4. There are 85 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 150 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRKACA	NM_002730.4	c.381G>A	p.Gly127=	synonymous_variant	5/10	ENST00000308677.9
PRKACA	NM_001304349.2	c.609G>A	p.Gly203=	synonymous_variant	5/10
PRKACA	NM_207518.3	c.357G>A	p.Gly119=	synonymous_variant	5/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKACA	ENST00000308677.9	c.381G>A	p.Gly127=	synonymous_variant	5/10	1	NM_002730.4	P1

Frequencies

GnomAD3 genomes AF: 0.000985 AC: 150 AN: 152228 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0229

Gnomad SAS AF: 0.00352

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00157 AC: 395 AN: 251378 Hom.: 6 AF XY: 0.00151 AC XY: 205 AN XY: 135904

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.0168

Gnomad SAS exome AF: 0.00157

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000255

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000767 AC: 1121 AN: 1461828 Hom.: 12 Cov.: 30 AF XY: 0.000840 AC XY: 611 AN XY: 727212

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0189

Gnomad4 SAS exome AF: 0.00188

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000109

Gnomad4 OTH exome AF: 0.00134

GnomAD4 genome AF: 0.000978 AC: 149 AN: 152346 Hom.: 4 Cov.: 32 AF XY: 0.00114 AC XY: 85 AN XY: 74494

Gnomad4 AFR AF: 0.0000240

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0227

Gnomad4 SAS AF: 0.00352

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000147 Hom.: 0

Bravo AF: 0.000846

Asia WGS AF: 0.0130 AC: 45 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.0000593

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

Invitae

Dec 31, 2019

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
Cadd	Benign	7.0
Dann	Benign	0.43
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: rs78098302; hg19: chr19-14211676; COSMIC: COSV58069534; COSMIC: COSV58069534;