rs2041980

Variant names:

• chr17-68481877-G-A
• rs2041980
• NM_001278433.2:c.-6-33517G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001278433.2(PRKAR1A):​c.-6-33517G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.109 in 152,300 control chromosomes in the GnomAD database, including 931 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.11 (931 hom., cov: 33)
• Consequence: PRKAR1A NM_001278433.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.25
• Publications: 5 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.115 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKAR1A	NM_001278433.2	c.-6-33517G>A		intron_variant	Intron 1 of 10		NP_001265362.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENSG00000267009	ENST00000586515.5	n.541-11762G>A		intron_variant	Intron 3 of 3	5
ENSG00000267009	ENST00000590353.1	n.174-33517G>A		intron_variant	Intron 1 of 5	4

Frequencies

GnomAD3 genomes AF: 0.109 AC: 16651 AN: 152182 Hom.: 930 Cov.: 33

Gnomad AFR AF: 0.0898

Gnomad AMI AF: 0.151

Gnomad AMR AF: 0.101

Gnomad ASJ AF: 0.0974

Gnomad EAS AF: 0.105

Gnomad SAS AF: 0.0847

Gnomad FIN AF: 0.157

Gnomad MID AF: 0.136

Gnomad NFE AF: 0.117

Gnomad OTH AF: 0.125

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.109 AC: 16651 AN: 152300 Hom.: 931 Cov.: 33 AF XY: 0.110 AC XY: 8195 AN XY: 74468

African (AFR) AF: 0.0896 AC: 3727 AN: 41576

American (AMR) AF: 0.100 AC: 1535 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0974 AC: 338 AN: 3470

East Asian (EAS) AF: 0.106 AC: 548 AN: 5188

South Asian (SAS) AF: 0.0856 AC: 413 AN: 4824

European-Finnish (FIN) AF: 0.157 AC: 1668 AN: 10604

Middle Eastern (MID) AF: 0.136 AC: 40 AN: 294

European-Non Finnish (NFE) AF: 0.117 AC: 7982 AN: 68020

Other (OTH) AF: 0.124 AC: 262 AN: 2114

Alfa AF: 0.112 Hom.: 708

Bravo AF: 0.104

Asia WGS AF: 0.0650 AC: 228 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.6
DANN	Benign	0.78
PhyloP100		1.2

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2041980; hg19: chr17-66478018;