rs200069356

chr17-68522799-G-Achr17-68522799-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BS1 BS2

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. R74C) 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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:7
• Conservation: PhyloP100: 4.85

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• PP2: Missense variant where missense usually causes diseases, PRKAR1A
• 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 id is 239382.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=7}. Variant chr17-68522799-G-A is described in Lovd as [Likely_benign].
• 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 male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 63 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRKAR1A	NM_002734.5	c.221G>A	p.Arg74His	missense_variant	3/11	ENST00000589228.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKAR1A	ENST00000589228.6	c.221G>A	p.Arg74His	missense_variant	3/11	1	NM_002734.5	P1
	ENST00000590353.1	n.400G>A		non_coding_transcript_exon_variant	3/6	4

Frequencies

GnomAD3 genomes AF: 0.000414 AC: 63 AN: 152202 Hom.: 1 Cov.: 32

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

GnomAD3 exomes AF: 0.000414 AC: 104 AN: 251254 Hom.: 0 AF XY: 0.000346 AC XY: 47 AN XY: 135792

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 SAS exome AF: 0.000653

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.: 0 Cov.: 31 AF XY: 0.000281 AC XY: 204 AN XY: 727190

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.00101

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000236

Gnomad4 OTH exome AF: 0.000596

GnomAD4 genome AF: 0.000407 AC: 62 AN: 152320 Hom.: 1 Cov.: 32 AF XY: 0.000416 AC XY: 31 AN XY: 74490

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.00137

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00186

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000279

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.000225 Hom.: 0

Bravo AF: 0.000465

ExAC AF: 0.000354 AC: 43

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Carney complex, type 1 Uncertain:2 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 28, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Sep 16, 2021	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. -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 07, 2023	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. -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 07, 2019	- -

Hereditary cancer-predisposing syndrome Benign:2

Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	May 07, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	May 10, 2022	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 condition Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 19, 2023

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

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.12
Cadd	Uncertain	23
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	D
LIST_S2	Benign	0.81	T;.;T;T;.;.;T;T;T;.;T;T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.038	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.36	T
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Benign	0.38	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	T
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.042
gMVP		0.35

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

Other links and lift over

dbSNP: rs200069356; hg19: chr17-66518940; COSMIC: COSV62235517; COSMIC: COSV62235517;