17-68524053-G-T

Position:

chr17-68524053-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP2

The NM_002734.5(PRKAR1A):c.478G>T(p.Ala160Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,752 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

PRKAR1A
NM_002734.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 10.0

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:

PRKAR1A (HGNC:):

PRKAR1A links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRKAR1A	NM_002734.5 linkuse as main transcript	c.478G>T	p.Ala160Ser	missense_variant	5/11	ENST00000589228.6	NP_002725.1	P10644-1B2R5T5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRKAR1A	ENST00000589228.6 linkuse as main transcript	c.478G>T	p.Ala160Ser	missense_variant	5/11	1	NM_002734.5	ENSP00000464977.2		P10644-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251400

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135876

show subpopulations

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 SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461752

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727174

show subpopulations

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:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Carney complex, type 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 29, 2021

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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with PRKAR1A-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with serine at codon 160 of the PRKAR1A protein (p.Ala160Ser). The alanine residue is highly conserved and there is a moderate physicochemical difference between alanine and serine. -

Hereditary cancer-predisposing syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 26, 2023

The p.A160S variant (also known as c.478G>T), located in coding exon 4 of the PRKAR1A gene, results from a G to T substitution at nucleotide position 478. The alanine at codon 160 is replaced by serine, an amino acid with similar properties. This amino acid position is conserved. 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

0.096

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

0.040

CADD

Pathogenic

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.44

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

Eigen

Benign

0.11

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Benign

0.84

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

M_CAP

Benign

0.069

MetaRNN

Uncertain

0.52

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

MetaSVM

Uncertain

0.094

MutationAssessor

Benign

1.9

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

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-1.2

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

REVEL

Uncertain

0.38

Sift

Benign

0.16

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

Sift4G

Benign

0.29

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

Polyphen

0.0

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

Vest4

0.73, 0.73, 0.73, 0.73, 0.74

MutPred

0.36

Gain of glycosylation at A160 (P = 0.0391);Gain of glycosylation at A160 (P = 0.0391);Gain of glycosylation at A160 (P = 0.0391);Gain of glycosylation at A160 (P = 0.0391);Gain of glycosylation at A160 (P = 0.0391);Gain of glycosylation at A160 (P = 0.0391);Gain of glycosylation at A160 (P = 0.0391);Gain of glycosylation at A160 (P = 0.0391);Gain of glycosylation at A160 (P = 0.0391);Gain of glycosylation at A160 (P = 0.0391);

MVP

0.90

MPC

1.2

ClinPred

0.56

GERP RS

6.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.9

Varity_R

0.14

gMVP

0.86

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

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