rs281864799

Positions:

• chr17-68528994-A-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

The ENST00000589228.6(PRKAR1A):​c.891+3A>G variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PRKAR1A ENST00000589228.6 splice_donor_region, intron
• Scores: Splicing: ADA: 0.9975
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 1.30

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-68528994-A-G is Pathogenic according to our data. Variant chr17-68528994-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 12664.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.891+3A>G		splice_donor_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.891+3A>G		splice_donor_region_variant, intron_variant		1	NM_002734.5	ENSP00000464977	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Carney complex, type 1 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2000	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	This sequence change falls in intron 9 of the PRKAR1A gene. It does not directly change the encoded amino acid sequence of the PRKAR1A protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with Carney complex (PMID: 10973256, 21900385; Invitae). ClinVar contains an entry for this variant (Variation ID: 12664). Studies have shown that this variant alters PRKAR1A gene expression (PMID: 21900385). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jul 09, 2024

Not observed at significant frequency in large population cohorts (gnomAD); Functional studies are inconclusive: only wildtype mRNA detected in tumor cells possibly due to elimination of mutant RNAs, decreased activated PKA in tumor cells (PMID: 10973256); In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 31589614, 10973256, 20358582, 24512486, 18419788, 21047926, 16569736, 21900385) -

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 20, 2024

The c.891+3A>G intronic variant results from an A to G substitution 3 nucleotides after coding exon 8 in the PRKAR1A gene. This variant was identified in a female proband who had several major and minor diagnostic clinical features of Carney complex (CNC) (Ambry internal data, external communication). This variant was also identified in a male proband with CNC who had lentiginosis, large-cell calcifying Sertoli cell tumor, and an acinar cell carcinoma (Gaujoux S et al. J Clin Endocrinol Metab. 2011 Nov;96 (11):1888–95). In another report, CNC tumors from a patient with this variant showed protein kinase A activity increased in response to cAMP compared with non-CNC tumors and that increase was blocked by protein kinase inhibitor (Kirschner L et al. Nature Genetics 26, 89–92 (2000)). This nucleotide position is not well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice donor site; however, direct evidence is insufficient at this time (Ambry internal data). Loss-of-function variants subject to nonsense mediated decay (NMD) in PRKAR1A are known to cause Carney complex; however, such associations with acrodysostosis have not been reported (Michot. et al. Eur J Hum Genet 26, 1611–1622 (2018)); Bertherat J et al. J Clin Endocrinol Metab. 2009 Jun;94(6):2085-91; Jafari N et al. Proc Natl Acad Sci U S A. 2021 May 25;118(21):e2024716118). Based on the supporting evidence, this alteration is likely pathogenic for Carney complex; however, the association of this alteration with acrodysostosis is unlikely. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Pathogenic	35
DANN	Benign	0.89
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.89
SpliceAI score (max)		0.93		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.93		Position offset: 33

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs281864799; hg19: chr17-66525135;