rs281864790

Positions:

chr17-68524063-CTG-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_002734.5(PRKAR1A):c.491_492del(p.Val164AspfsTer5) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,613,890 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. T163T) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

PRKAR1A
NM_002734.5 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4O:1

Conservation

PhyloP100: 10.0

Variant links:

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]

PRKAR1A links:

(HGNC:):

links:

Genome browser will be placed here

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 17-68524063-CTG-C is Pathogenic according to our data. Variant chr17-68524063-CTG-C is described in ClinVar as [Pathogenic]. Clinvar id is 12662.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-68524063-CTG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRKAR1A	NM_002734.5 linkuse as main transcript	c.491_492del	p.Val164AspfsTer5	frameshift_variant	5/11	ENST00000589228.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKAR1A	ENST00000589228.6 linkuse as main transcript	c.491_492del	p.Val164AspfsTer5	frameshift_variant	5/11	1	NM_002734.5	P1	P10644-1
	ENST00000590353.1 linkuse as main transcript	n.670_671del		non_coding_transcript_exon_variant	5/6	4

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152106

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251428

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135884

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461784

Hom.:

AF XY:

0.00000138

AC XY:

AN XY:

727196

show subpopulations

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152106

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74294

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

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:2Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2000	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 01, 2023	This sequence change creates a premature translational stop signal (p.Val164Aspfs*5) 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 present in population databases (rs281864790, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with Carney complex (PMID: 10973256, 24088910, 25890363). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is also known as 578delTG. ClinVar contains an entry for this variant (Variation ID: 12662). For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Feb 24, 2023

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Also known as c.578delTG; This variant is associated with the following publications: (PMID: 35034934, 29561454, 10973256, 19429701, 19293268, 25890363, 22259056, 24088910, 30882689, 32011755) -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 08, 2022

The c.491_492delTG pathogenic mutation, located in coding exon 4 of the PRKAR1A gene, results from a deletion of two nucleotides at nucleotide positions 491 to 492, causing a translational frameshift with a predicted alternate stop codon (p.V164Dfs*5). This alteration has been observed in multiple individuals who exhibit two or more of the major clinical diagnostic criteria for Carney complex (Kirschner LS et al. Nat Genet, 2000 Sep;26:89-92; Almeida MQ et al. J Clin Endocrinol Metab, 2012 Apr;97:E687-93; Briassoulis G et al. J Stroke Cerebrovasc Dis, 2012 Nov;21:914.e1-8; Havrankova E et al. Ann Thorac Cardiovasc Surg, 2014 Oct;20 Suppl:890-2; Guo H et al. World J Surg Oncol, 2015 Feb;13:83; Wang L et al. Medicine (Baltimore), 2018 Mar;97:e0247; Tirosh A et al. Horm Res Paediatr, 2018 Nov;89:38-46; Ma S et al. Medicine (Baltimore), 2019 Mar;98:e14866; Tsurutani Y et al. Intern Med, 2022 Jan;61:205-211). 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). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on the supporting evidence, this alteration is 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

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over