rs1555813215
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP2PP3
The NM_002734.5(PRKAR1A):c.287G>A(p.Arg96Gln) 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 Uncertain significance (★★).
Frequency
Genomes: not found (cov: 32)
Consequence
PRKAR1A
NM_002734.5 missense
NM_002734.5 missense
Scores
10
7
2
Clinical Significance
Conservation
PhyloP100: 10.0
Genes affected
PRKAR1A (HGNC:9388): (protein kinase cAMP-dependent type I regulatory subunit alpha) cAMP is a signaling molecule important for a variety of cellular functions. cAMP exerts its effects by activating the cAMP-dependent protein kinase, which transduces the signal through phosphorylation of different target proteins. The inactive kinase holoenzyme is a tetramer composed of two regulatory and two catalytic subunits. 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. This gene encodes one of the regulatory subunits. This protein was found to be a tissue-specific extinguisher that down-regulates the expression of seven liver genes in hepatoma x fibroblast hybrids. Mutations in this gene cause Carney complex (CNC). This gene can fuse to the RET protooncogene by gene rearrangement and form the thyroid tumor-specific chimeric oncogene known as PTC2. A nonconventional nuclear localization sequence (NLS) has been found for this protein which suggests a role in DNA replication via the protein serving as a nuclear transport protein for the second subunit of the Replication Factor C (RFC40). Several alternatively spliced transcript variants encoding two different isoforms have been observed. [provided by RefSeq, Jan 2013]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 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), PRKAR1A. . Gene score misZ 3.1236 (greater than the threshold 3.09). Trascript score misZ 4.1467 (greater than threshold 3.09). GenCC has associacion of gene with acrodysostosis with multiple hormone resistance, pigmented nodular adrenocortical disease, primary, 1, primary pigmented nodular adrenocortical disease, acrodysostosis, Carney complex, Acrodysostosis 1 with or without hormone resistance, Carney complex, type 1, familial atrial myxoma.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.794
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PRKAR1A | NM_002734.5 | c.287G>A | p.Arg96Gln | missense_variant | 3/11 | ENST00000589228.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PRKAR1A | ENST00000589228.6 | c.287G>A | p.Arg96Gln | missense_variant | 3/11 | 1 | NM_002734.5 | P1 | |
ENST00000590353.1 | n.466G>A | non_coding_transcript_exon_variant | 3/6 | 4 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Carney complex, type 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | May 12, 2021 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with PRKAR1A-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with glutamine at codon 96 of the PRKAR1A protein (p.Arg96Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 13, 2024 | The c.287G>A (p.R96Q) alteration is located in exon 3 (coding exon 2) of the PRKAR1A gene. This alteration results from a G to A substitution at nucleotide position 287, causing the arginine (R) at amino acid position 96 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Benign
T;D;D;T;D;D;T;.;T;D;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;.;D;D;.;.;D;D;D;.;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
.;M;M;.;M;M;.;.;.;M;.;M
MutationTaster
Benign
D;D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
.;D;D;.;.;D;.;.;.;.;.;.
REVEL
Uncertain
Sift
Uncertain
.;D;D;.;.;D;.;.;.;.;.;.
Sift4G
Uncertain
D;D;D;D;D;D;D;D;D;D;D;D
Polyphen
1.0
.;D;D;.;D;D;.;.;.;D;.;.
Vest4
0.68, 0.68, 0.69
MutPred
Loss of MoRF binding (P = 0.0442);Loss of MoRF binding (P = 0.0442);Loss of MoRF binding (P = 0.0442);Loss of MoRF binding (P = 0.0442);Loss of MoRF binding (P = 0.0442);Loss of MoRF binding (P = 0.0442);Loss of MoRF binding (P = 0.0442);Loss of MoRF binding (P = 0.0442);Loss of MoRF binding (P = 0.0442);Loss of MoRF binding (P = 0.0442);Loss of MoRF binding (P = 0.0442);Loss of MoRF binding (P = 0.0442);
MVP
MPC
2.7
ClinPred
D
GERP RS
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