rs727503379

Positions:

• chr17-68525825-TG-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• 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]

ACMG classification

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

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461740 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727168

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: 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	- -
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

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs727503379; hg19: chr17-66521966;