chr17-68525775-G-A

Position:

• chr17-68525775-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1 PM2 PP2 BP4

The NM_002734.5(PRKAR1A):​c.571G>A​(p.Ala191Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PRKAR1A NM_002734.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 8.19

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a binding_site (size 117) in uniprot entity KAP0_HUMAN there are 8 pathogenic changes around while only 1 benign (89%) in NM_002734.5
• PM2: Very rare variant in population databases, with high coverage
• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.41507614).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRKAR1A	NM_002734.5	c.571G>A	p.Ala191Thr	missense_variant	7/11	ENST00000589228.6	NP_002725.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRKAR1A	ENST00000589228.6	c.571G>A	p.Ala191Thr	missense_variant	7/11	1	NM_002734.5	ENSP00000464977.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1461740 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727182

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Acrodysostosis 1 with or without hormone resistance Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Sep 12, 2023

- -

Carney complex, type 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 25, 2022

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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PRKAR1A protein function. ClinVar contains an entry for this variant (Variation ID: 536888). This variant has not been reported in the literature in individuals affected with PRKAR1A-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 191 of the PRKAR1A protein (p.Ala191Thr). -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 13, 2023

The p.A191T variant (also known as c.571G>A), located in coding exon 6 of the PRKAR1A gene, results from a G to A substitution at nucleotide position 571. The alanine at codon 191 is replaced by threonine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	T;D;D;D;D;.;D;.
Eigen	Benign	0.13
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.86	D;.;D;.;.;D;.;D
M_CAP	Benign	0.072	D
MetaRNN	Benign	0.42	T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.063	T
MutationAssessor	Benign	0.060	.;N;N;N;N;.;N;N
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.46	.;N;N;.;N;.;.;.
REVEL	Uncertain	0.41
Sift	Uncertain	0.021	.;D;D;.;D;.;.;.
Sift4G	Uncertain	0.029	D;D;D;D;D;D;D;D
Polyphen		0.0010	.;B;B;B;B;.;B;.
Vest4		0.47, 0.47, 0.47, 0.47
MutPred		0.50		Gain of glycosylation at A191 (P = 0.014);Gain of glycosylation at A191 (P = 0.014);Gain of glycosylation at A191 (P = 0.014);Gain of glycosylation at A191 (P = 0.014);Gain of glycosylation at A191 (P = 0.014);Gain of glycosylation at A191 (P = 0.014);Gain of glycosylation at A191 (P = 0.014);Gain of glycosylation at A191 (P = 0.014);
MVP		0.76
MPC		1.3
ClinPred		0.75	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.10
gMVP		0.74

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: rs1555814054; hg19: chr17-66521916;