rs2041980

Positions:

• chr17-68481877-G-A

Variant summary

Our verdict is Benign. Variant got -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

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]

ENSG00000267009 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
PRKAR1A	NM_001278433.2	c.-6-33517G>A		intron_variant			NP_001265362.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ENSG00000267009	ENST00000586515.5	n.541-11762G>A		intron_variant		5
ENSG00000267009	ENST00000590353.1	n.174-33517G>A		intron_variant		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

Gnomad4 AFR AF: 0.0896

Gnomad4 AMR AF: 0.100

Gnomad4 ASJ AF: 0.0974

Gnomad4 EAS AF: 0.106

Gnomad4 SAS AF: 0.0856

Gnomad4 FIN AF: 0.157

Gnomad4 NFE AF: 0.117

Gnomad4 OTH AF: 0.124

Alfa AF: 0.112 Hom.: 648

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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs2041980; hg19: chr17-66478018;