rs756985434
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PP2PP3BS2_Supporting
The NM_002734.5(PRKAR1A):c.94A>G(p.Lys32Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,613,416 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000048 ( 0 hom. )
Consequence
PRKAR1A
NM_002734.5 missense
NM_002734.5 missense
Scores
8
7
4
Clinical Significance
Conservation
PhyloP100: 9.32
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 1 ACMG points.
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, 0.764
BS2
High AC in GnomAdExome4 at 7 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PRKAR1A | NM_002734.5 | c.94A>G | p.Lys32Glu | missense_variant | 2/11 | ENST00000589228.6 | NP_002725.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PRKAR1A | ENST00000589228.6 | c.94A>G | p.Lys32Glu | missense_variant | 2/11 | 1 | NM_002734.5 | ENSP00000464977 | P1 | |
ENST00000590353.1 | n.273A>G | non_coding_transcript_exon_variant | 2/6 | 4 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152234Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251424Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135890
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GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461182Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3AN XY: 726908
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152234Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74372
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Acrodysostosis 1 with or without hormone resistance Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Nov 30, 2023 | - - |
Carney complex, type 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 15, 2024 | This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 32 of the PRKAR1A protein (p.Lys32Glu). This variant is present in population databases (rs756985434, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with PRKAR1A-related conditions. ClinVar contains an entry for this variant (Variation ID: 469080). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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. - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 24, 2023 | The p.K32E variant (also known as c.94A>G), located in coding exon 1 of the PRKAR1A gene, results from an A to G substitution at nucleotide position 94. The lysine at codon 32 is replaced by glutamic acid, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, 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
Uncertain
DEOGEN2
Benign
T;T;T;T;T;T;T;.;.;T;T;T;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;.;D;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;D;D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
.;M;M;.;M;M;.;.;.;.;.;M;.;M
MutationTaster
Benign
D;D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Benign
.;N;N;.;.;N;.;.;.;.;.;.;.;.
REVEL
Pathogenic
Sift
Uncertain
.;D;D;.;.;D;.;.;.;.;.;.;.;.
Sift4G
Benign
T;T;T;D;T;T;D;D;T;D;D;T;D;T
Polyphen
1.0
.;D;D;.;D;D;.;.;.;.;.;D;.;.
Vest4
0.86, 0.77, 0.85
MutPred
Loss of ubiquitination at K32 (P = 0.0297);Loss of ubiquitination at K32 (P = 0.0297);Loss of ubiquitination at K32 (P = 0.0297);Loss of ubiquitination at K32 (P = 0.0297);Loss of ubiquitination at K32 (P = 0.0297);Loss of ubiquitination at K32 (P = 0.0297);Loss of ubiquitination at K32 (P = 0.0297);Loss of ubiquitination at K32 (P = 0.0297);Loss of ubiquitination at K32 (P = 0.0297);Loss of ubiquitination at K32 (P = 0.0297);Loss of ubiquitination at K32 (P = 0.0297);Loss of ubiquitination at K32 (P = 0.0297);Loss of ubiquitination at K32 (P = 0.0297);Loss of ubiquitination at K32 (P = 0.0297);
MVP
MPC
0.38
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at