chr19-14097604-A-C
Position:
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PP2PP3_StrongPP5
The NM_002730.4(PRKACA):c.617T>G(p.Leu206Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars).
Frequency
Genomes: not found (cov: 31)
Consequence
PRKACA
NM_002730.4 missense
NM_002730.4 missense
Scores
8
7
4
Clinical Significance
Conservation
PhyloP100: 9.09
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
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.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.95
PP5
Variant 19-14097604-A-C is Pathogenic according to our data. Variant chr19-14097604-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 91945.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr19-14097604-A-C is described in UniProt as null.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PRKACA | NM_002730.4 | c.617T>G | p.Leu206Arg | missense_variant | 7/10 | ENST00000308677.9 | NP_002721.1 | |
PRKACA | NM_001304349.2 | c.845T>G | p.Leu282Arg | missense_variant | 7/10 | NP_001291278.1 | ||
PRKACA | NM_207518.3 | c.593T>G | p.Leu198Arg | missense_variant | 7/10 | NP_997401.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PRKACA | ENST00000308677.9 | c.617T>G | p.Leu206Arg | missense_variant | 7/10 | 1 | NM_002730.4 | ENSP00000309591 | P1 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD3 genomes
Cov.:
31
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome Cov.: 31
GnomAD4 genome
Cov.:
31
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
ACTH-independent adrenal Cushing syndrome, somatic Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 01, 2014 | - - |
Pigmented nodular adrenocortical disease, primary, 4 Pathogenic:1
Pathogenic, no assertion criteria provided | research | Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München | Mar 13, 2014 | - - |
not provided Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Richard Lifton Laboratory, Yale University School of Medicine | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
T;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;T
M_CAP
Benign
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Benign
T
MutationAssessor
Benign
L;.;.
MutationTaster
Benign
D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;.;.
REVEL
Uncertain
Sift
Pathogenic
D;.;.
Sift4G
Pathogenic
D;D;D
Polyphen
D;D;D
Vest4
MutPred
Gain of methylation at L206 (P = 0.0234);.;.;
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at