rs281864782

Variant names:

• chr17-68515523-C-G
• rs281864782
• NM_002734.5:c.124C>G

Your query was ambiguous. Multiple possible variants found:

• chr17-68515523-C-G
• chr17-68515523-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_002734.5(PRKAR1A):​c.124C>G​(p.Arg42Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,810 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. R42Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PRKAR1A NM_002734.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.17
• Publications: 8 publications found

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

ENSG00000267009 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKAR1A	NM_002734.5	c.124C>G	p.Arg42Gly	missense_variant	Exon 2 of 11	ENST00000589228.6	NP_002725.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRKAR1A	ENST00000589228.6	c.124C>G	p.Arg42Gly	missense_variant	Exon 2 of 11	1	NM_002734.5	ENSP00000464977.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251388 AF XY: 0.0000147

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460810 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726728

African (AFR) AF: 0.00 AC: 0 AN: 33444

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86168

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4944

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111986

Other (OTH) AF: 0.0000166 AC: 1 AN: 60296

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Carney complex, type 1 Uncertain:1

May 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 42 of the PRKAR1A protein (p.Arg42Gly). This variant is present in population databases (rs281864782, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with PRKAR1A-related conditions. ClinVar contains an entry for this variant (Variation ID: 1504882). 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 disruptive. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Uncertain	0.020	T
BayesDel_noAF	Benign	-0.11
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	T;D;D;T;D;D;T;.;.;T;T;D;.;.
Eigen	Benign	0.020
Eigen_PC	Benign	-0.029
FATHMM_MKL	Benign	0.65	D
LIST_S2	Uncertain	0.91	D;.;D;D;.;.;D;D;D;D;D;.;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.64	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.063	D
MutationAssessor	Uncertain	2.2	.;M;M;.;M;M;.;.;.;.;.;M;.;M
PhyloP100		2.2
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-2.9	.;D;D;.;.;D;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.50
Sift	Uncertain	0.0020	.;D;D;.;.;D;.;.;.;.;.;.;.;.
Sift4G	Uncertain	0.045	D;D;D;D;D;D;T;D;D;T;D;D;D;D
Polyphen		0.52	.;P;P;.;P;P;.;.;.;.;.;P;.;.
Vest4		0.82, 0.82, 0.66, 0.79
MutPred		0.58		Gain of catalytic residue at A41 (P = 0.0296);Gain of catalytic residue at A41 (P = 0.0296);Gain of catalytic residue at A41 (P = 0.0296);Gain of catalytic residue at A41 (P = 0.0296);Gain of catalytic residue at A41 (P = 0.0296);Gain of catalytic residue at A41 (P = 0.0296);Gain of catalytic residue at A41 (P = 0.0296);Gain of catalytic residue at A41 (P = 0.0296);Gain of catalytic residue at A41 (P = 0.0296);Gain of catalytic residue at A41 (P = 0.0296);Gain of catalytic residue at A41 (P = 0.0296);Gain of catalytic residue at A41 (P = 0.0296);Gain of catalytic residue at A41 (P = 0.0296);Gain of catalytic residue at A41 (P = 0.0296);
MVP		0.76
MPC		0.46
ClinPred		0.96	D
GERP RS		4.1
PromoterAI		-0.014	Neutral
Varity_R		0.90
gMVP		0.76

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

Other links and lift over

dbSNP: rs281864782; hg19: chr17-66511664;