rs727503379
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_002734.5(PRKAR1A):c.623del(p.Gly208GlufsTer14) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,740 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
PRKAR1A
NM_002734.5 frameshift
NM_002734.5 frameshift
Scores
Not classified
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 Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 17-68525825-TG-T is Pathogenic according to our data. Variant chr17-68525825-TG-T is described in ClinVar as [Pathogenic]. Clinvar id is 164995.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PRKAR1A | NM_002734.5 | c.623del | p.Gly208GlufsTer14 | frameshift_variant | 7/11 | ENST00000589228.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PRKAR1A | ENST00000589228.6 | c.623del | p.Gly208GlufsTer14 | frameshift_variant | 7/11 | 1 | NM_002734.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
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32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461740Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727168
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727168
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GnomAD4 genome ? Cov.: 32
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Carney complex, type 1 Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 01, 2000 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Feb 23, 2022 | This sequence change creates a premature translational stop signal (p.Gly208Glufs*14) in the PRKAR1A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PRKAR1A are known to be pathogenic (PMID: 11115848, 19293268). This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 164995). This variant is also known as ∆FSterGly208. This premature translational stop signal has been observed in individual(s) with Carney complex (PMID: 10974026). - |
Carney complex Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 09, 2014 | The Gly208fs variant in PRKAR1A has been previously reported in one family with Carney complex (Casey 1998, Casey 2000) but was absent from large population stu dies. This frameshift variant is predicted to alter the protein?s amino acid seq uence beginning at position 208 and lead to a premature termination codon 14 ami no acids downstream. This alteration is then predicted to lead to a truncated or absent protein. This prediction is further supported by functional analyses (Ca sey 2000). Loss of function of the PRKAR1A gene is an established disease mechan ism in individuals with Carney complex (Kirschner, 2000). In summary, this varia nt meets our criteria to be classified as pathogenic (http://pcpgm.partners.org/ LMM). - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 14, 2016 | The c.623delG variant in the PRKAR1A gene has been reported previously in association Carney complex, where it was shown to result in decreased R1α protein in lymphocytes (Casey et al., 2000). The c.623delG deletion causes a frameshift starting with codon Glycine 208 , changes this amino acid to a Glutamic acid residue and creates a premature Stop codon at position 14 of the new reading frame, denoted p.Gly208GlufsX14. This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. In addition, the c.623delG variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. Therefore, we consider c.623delG to be a pathogenic variant. - |
Computational scores
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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