rs137853303

Positions:

chr17-68522798-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2BS2

The NM_002734.5(PRKAR1A):c.220C>T(p.Arg74Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000335 in 1,613,940 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R74H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000035 ( 0 hom. )

Consequence

PRKAR1A
NM_002734.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:7

Conservation

PhyloP100: 7.91

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 Likely_benign. Variant got -3 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PRKAR1A. . Gene score misZ 3.1236 (greater than the threshold 3.09). Trascript score misZ 4.1467 (greater than threshold 3.09). GenCC has associacion of gene with acrodysostosis with multiple hormone resistance, pigmented nodular adrenocortical disease, primary, 1, primary pigmented nodular adrenocortical disease, acrodysostosis, Carney complex, Acrodysostosis 1 with or without hormone resistance, Carney complex, type 1, familial atrial myxoma.

BS2

High AC in GnomAdExome4 at 51 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRKAR1A	NM_002734.5 linkuse as main transcript	c.220C>T	p.Arg74Cys	missense_variant	3/11	ENST00000589228.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKAR1A	ENST00000589228.6 linkuse as main transcript	c.220C>T	p.Arg74Cys	missense_variant	3/11	1	NM_002734.5	P1	P10644-1
	ENST00000590353.1 linkuse as main transcript	n.399C>T		non_coding_transcript_exon_variant	3/6	4

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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:

0.00000796

AC:

AN:

251268

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135804

show subpopulations

Gnomad AFR exome

AF:

0.000123

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000349

AC:

AN:

1461802

Hom.:

Cov.:

AF XY:

0.0000385

AC XY:

AN XY:

727196

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

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:

0.0000441

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152138

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74310

show subpopulations

Gnomad4 AFR

AF:

0.0000483

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

Alfa

AF:

0.0000347

Hom.:

Bravo

AF:

0.0000340

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Carney complex, type 1

Pathogenic:1Uncertain:1

Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2008	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Nov 28, 2023	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 74 of the PRKAR1A protein (p.Arg74Cys). This variant is present in population databases (rs137853303, gnomAD 0.01%). This missense change has been observed in individual(s) with Carney complex (PMID: 15371594). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12674). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on PRKAR1A function (PMID: 15371594, 18241045). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Hereditary cancer-predisposing syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 19, 2023	The p.R74C variant (also known as c.220C>T), located in coding exon 2 of the PRKAR1A gene, results from a C to T substitution at nucleotide position 220. The arginine at codon 74 is replaced by cysteine, an amino acid with highly dissimilar properties. The p.R74C variant was first reported in an English proband with clinical features of Carney complex such as cardiac myxoma, lentiginosis, breast myxofibroma, thyroid adenoma, pulmonic stenosis, and deafness. Functional studies were also performed to measure basal as well as cAMP-stimulated protein kinase A (PKA) activity in lymphoblasts from this proband and in an in vitro luciferase-reporter assay. Results demonstrated activity levels for this variant were not significantly different than those for wild type PRKAR1A (Veugelers M et al. Proc. Natl. Acad. Sci. U.S.A., 2004 Sep;101:14222-7). In another functional study, this variant was reported to be associated with increased PKA activity and increased PKA-specific activation in assays performed in vitro. Furthermore, the PRKAR1A RIα regulatory subunit, which harbors p.R74C, demonstrated reduced binding with both cAMP and the PRKAR1A Cα catalytic subunit (Greene EL et al. Hum. Mutat., 2008 May;29:633-9). This variant was also identified in an exome cohort, but the clinical history of the proband was not provided (Amendola LM et al. Genome Res., 2015 Mar;25:305-15). Based on an internal structural assessment, this alteration results in loss of a predicted phosphorylation motif ([RK]..[ST]) that may be necessary for the functionally confirmed phosphorylation of Ser77 (Han YS et al. Arch. Biochem. Biophys., 2013 Oct;538:25-33). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Jun 03, 2021	- -

Acrodysostosis 1 with or without hormone resistance

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Dec 04, 2023

- -

Carney complex

Uncertain:1

Uncertain significance, no assertion criteria provided

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Feb 14, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies are conflicting: one study demonstrates protein expression levels and protein kinase A (PKA) activity similar to wildtype, while another shows increased PKA activity possibly due to decreased binding of cAMP (Veugelers et al., 2004; Greene et al., 2008); This variant is associated with the following publications: (PMID: 26130139, 23942052, 21111774, 20358582, 15992699, 19650827, 21115159, 29264456, 22112814, 15371594, 18241045, 25637381, 18760947, 16491075) -

PRKAR1A-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 18, 2023

The PRKAR1A c.220C>T variant is predicted to result in the amino acid substitution p.Arg74Cys. This variant was reported to segregate in a family with Carney complex (Figure S5, Veugelers et al. 2004. PubMed ID: 15371594). Functional studies using patient-derived lymphoblastoid cell lines showed that this variant does not significantly alter basal or cAMP-stimulated protein kinase A (PKA) activity (Veugelers et al. 2004. PubMed ID: 15371594). However, a different study showed that this variant leads to decreased binding to cAMP and increased PKA activity (Greene et al. 2008. PubMed ID: 18241045). This variant is reported in 0.012% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-66518939-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.41

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.022

T;D;D;T;D;D;T;.;T;D;.;.

Eigen

Benign

0.030

Eigen_PC

Benign

0.20

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.89

D;.;D;D;.;.;D;D;D;.;D;D

M_CAP

Uncertain

0.098

MetaRNN

Uncertain

0.68

D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Benign

-0.28

MutationAssessor

Benign

1.2

.;L;L;.;L;L;.;.;.;L;.;L

MutationTaster

Benign

1.0

A;A;A;A;A

PrimateAI

Benign

0.43

PROVEAN

Benign

-1.7

.;N;N;.;.;N;.;.;.;.;.;.

REVEL

Uncertain

0.47

Sift

Benign

0.034

.;D;D;.;.;D;.;.;.;.;.;.

Sift4G

Uncertain

0.042

D;T;T;D;T;T;D;T;D;T;D;T

Polyphen

0.0020

.;B;B;.;B;B;.;.;.;B;.;.

Vest4

0.49, 0.48, 0.52

MVP

0.99

MPC

1.8

ClinPred

0.46

GERP RS

6.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.15

gMVP

0.46

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

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