rs281864801
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Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_002734.5(PRKAR1A):c.709-7_709-2delTTTTTA variant causes a splice acceptor, splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000208 in 1,442,274 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )
Consequence
PRKAR1A
NM_002734.5 splice_acceptor, splice_region, intron
NM_002734.5 splice_acceptor, splice_region, intron
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 2.54
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 Pathogenic. Variant got 12 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.05235602 fraction of the gene. Cryptic splice site detected, with MaxEntScore 10, offset of 0 (no position change), new splice context is: atcacttttgttatttttAGgga. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 17-68527823-GTTATTT-G is Pathogenic according to our data. Variant chr17-68527823-GTTATTT-G is described in ClinVar as [Pathogenic]. Clinvar id is 12675.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PRKAR1A | NM_002734.5 | c.709-7_709-2delTTTTTA | splice_acceptor_variant, splice_region_variant, intron_variant | ENST00000589228.6 | NP_002725.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PRKAR1A | ENST00000589228.6 | c.709-7_709-2delTTTTTA | splice_acceptor_variant, splice_region_variant, intron_variant | 1 | NM_002734.5 | ENSP00000464977.2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 0.00000208 AC: 3AN: 1442274Hom.: 0 AF XY: 0.00000278 AC XY: 2AN XY: 718760
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GnomAD4 genome Cov.: 32
GnomAD4 genome
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32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:4Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Carney complex, type 1 Pathogenic:1Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 13, 2022 | This sequence change falls in intron 7 of the PRKAR1A gene. It does not directly change the encoded amino acid sequence of the PRKAR1A protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. For these reasons, this variant has been classified as Pathogenic. Studies have shown that this variant results in skipping of exon 8 (also called exon 7) and introduces a premature termination codon (PMID: 16464939). The resulting mRNA is expected to undergo nonsense-mediated decay. This variant is also known as exon 7 IVS del (-7_-2). This variant has been observed in individuals with clinical features of Carney complex, mostly presenting with primary pigmented nodular adrenocortical disease (PPNAD) (PMID: 16464939, 24859511, 29909407). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). - |
Pigmented nodular adrenocortical disease, primary, 1 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | May 01, 2006 | - - |
Pigmented nodular adrenocortical disease, primary, 1;C2607929:Carney complex, type 1;C2931787:Familial atrial myxoma;C3276228:Acrodysostosis 1 with or without hormone resistance Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 26, 2021 | - - |
CARNEY COMPLEX, TYPE I Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | May 01, 2006 | - - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at