NM_002734.5:c.221G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_002734.5(PRKAR1A):c.221G>A(p.Arg74His) variant causes a missense change. The variant allele was found at a frequency of 0.000294 in 1,614,122 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R74P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00041 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00028 ( 0 hom. )

Consequence

PRKAR1A
NM_002734.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:8

Conservation

PhyloP100: 4.85

Publications

8 publications found

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 Gene-Disease associations (from GenCC):

Acrodysostosis 1 with or without hormone resistance
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
acrodysostosis with multiple hormone resistance
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Illumina, Orphanet
Carney complex, type 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
pigmented nodular adrenocortical disease, primary, 1
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Genomics England PanelApp, Ambry Genetics
acrodysostosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Carney complex
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
familial atrial myxoma
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
primary pigmented nodular adrenocortical disease
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

PRKAR1A links:

ENSG00000267009 (HGNC:):

ENSG00000267009 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.03820449).

BP6

Variant 17-68522799-G-A is Benign according to our data. Variant chr17-68522799-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 239382.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000407 (62/152320) while in subpopulation SAS AF = 0.00186 (9/4830). AF 95% confidence interval is 0.000971. There are 1 homozygotes in GnomAd4. There are 31 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 62 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKAR1A	NM_002734.5 link	c.221G>A	p.Arg74His	missense_variant	Exon 3 of 11	ENST00000589228.6	NP_002725.1	P10644-1B2R5T5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRKAR1A	ENST00000589228.6 link	c.221G>A	p.Arg74His	missense_variant	Exon 3 of 11	1	NM_002734.5	ENSP00000464977.2		P10644-1

Frequencies

GnomAD3 genomes

AF:

0.000414

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00137

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000279

Gnomad OTH

AF:

0.00430

GnomAD2 exomes

AF:

0.000414

AC:

104

AN:

251254

AF XY:

0.000346

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00104

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000326

Gnomad OTH exome

AF:

0.00163

GnomAD4 exome

AF:

0.000283

AC:

413

AN:

1461802

Hom.:

Cov.:

AF XY:

0.000281

AC XY:

204

AN XY:

727190

show subpopulations

African (AFR)

AF:

0.0000597

AC:

AN:

33474

American (AMR)

AF:

0.00101

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.000696

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.00121

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000236

AC:

262

AN:

1111956

Other (OTH)

AF:

0.000596

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

102

127

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000407

AC:

AN:

152320

Hom.:

Cov.:

AF XY:

0.000416

AC XY:

AN XY:

74490

show subpopulations

African (AFR)

AF:

0.0000962

AC:

AN:

41562

American (AMR)

AF:

0.00137

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00186

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000279

AC:

AN:

68030

Other (OTH)

AF:

0.00426

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000225

Hom.:

Bravo

AF:

0.000465

ExAC

AF:

0.000354

AC:

Asia WGS

AF:

0.00318

AC:

AN:

3478

EpiCase

AF:

0.000436

EpiControl

AF:

0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Carney complex, type 1

Uncertain:1Benign:2

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Sep 16, 2021

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The PRKAR1A c.221GA (p.Arg74His) missense change has a maximum frequency of 0.10% in gnomAD v2.1.1 (BS1; https://gnomad.broadinstitute.org/variant/17-66518940-G-A). Although this frequency is higher than expected for a pathogenic variant associated with Carney complex (PMID: 20301463), this variant has been reported in an individual with Carney complex whose pituitary tumor demonstrated loss of heterozygosity (PMID: 29264456). It has also been reported in multiple individuals with a clinical presentation not suggestive of Carney complex (PMID: 28051113, 32443704, internal data). This variant occurs in a gene where missense variants are more likely to be damaging based on methods described by Lek et al. (PP2; PMID: 27535533). In silico tools are not in agreement about the effect of this variant on protein function. Functional studies of HEK293 cells transfected with a plasmid containing this variant indicated that this variant caused a modest increase in cAMP signaling (PMID: 20301463). In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: BS1, PP2. -

not specified

Benign:2

Jun 07, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: PRKAR1A c.221G>A (p.Arg74His) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00041 in 251254 control chromosomes (gnomAD). The observed variant frequency is approximately 220 fold of the estimated maximal expected allele frequency for a pathogenic variant in PRKAR1A causing Carney Complex phenotype (1.9e-06), strongly suggesting that the variant is benign. Although the variant c.221G>A has been reported in the literature in an individual affected with Ovarian cancer (Castellanos 2016), Carney Complex (Tsay 2017), and Pituitary adenomas (de LaPiscina_ 2021). At-least one of these individuals affected with Pituitary adenomas had a pathogenic co-occurrence in AIP gene, c.811C>T;p.R271W (de LaPiscina_ 2021). One of these studies (Tsay 2017), also performed a functional evaluation on the variant of interest, and found that the variant protein was expressed, and while it did not directly alter protein kinase A activity, an increased intracellular level of phosphorylated CREB was observed as a downstream effect; hence indicating an overall increase in cAMP signaling. However, this study does not allow a clearly convincing conclusion about the variant effect. The following publications have been ascertained in the context of this evaluation (PMID: 28051113, 29264456, 34313605). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely benign (n=5) or uncertain significance (n=2). Based on the evidence outlined above, the variant was classified as likely benign. -

Jun 07, 2019

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:2

May 07, 2021

Sema4, Sema4

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:curation

- -

May 10, 2022

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

PRKAR1A-related disorder

Uncertain:1

Dec 19, 2023

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The PRKAR1A c.221G>A variant is predicted to result in the amino acid substitution p.Arg74His. This variant has been reported in individuals with pituitary adenomas (Table 3, Martínez de LaPiscina et al. 2021. PubMed ID: 34313605; Tsay et al. 2017. PubMed ID: 29264456) and ovarian cancer (Castellanos et al. 2017. PubMed ID: 28051113). It has also been reported in individuals undergoing hereditary cancer testing (Table S1, Velázquez et al. 2020. PubMed ID: 32522261). This variant is reported in 0.10% of alleles in individuals of Latino descent in gnomAD, which may be too high to be a primary cause of disease and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/239382/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Acrodysostosis 1 with or without hormone resistance

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Hereditary cancer

Benign:1

Sep 11, 2024

Mendelics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following: it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease, and/or has normal protein function, and/or has lack of segregation with disease, and/or has been detected in co-occurrence with known pathogenic variant, and/or has lack of disease association in case-control studies, and/or is located in a region inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.12

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0098

T;T;T;T;T;T;T;.;T;T;.;.

Eigen

Benign

-0.0041

Eigen_PC

Benign

0.10

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.81

T;.;T;T;.;.;T;T;T;.;T;T

M_CAP

Benign

0.029

MetaRNN

Benign

0.038

T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.36

MutationAssessor

Benign

0.90

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

PhyloP100

4.8

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.53

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

REVEL

Uncertain

0.38

Sift

Benign

0.20

.;T;T;.;.;T;.;.;.;.;.;.

Sift4G

Benign

0.10

T;T;T;T;T;T;T;T;T;T;T;T

Polyphen

0.56

.;P;P;.;P;P;.;.;.;P;.;.

Vest4

0.23, 0.24

MVP

0.75

MPC

1.6

ClinPred

0.036

GERP RS

3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.042

gMVP

0.35

Mutation Taster

=56/44

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over