17-68512102-C-A

Position:

• chr17-68512102-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000358598(PRKAR1A):​c.-47C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.73 in 154,190 control chromosomes in the GnomAD database, including 41,315 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.73 (40657 hom., cov: 31)
  • Exomes 𝑓: 0.76 (658 hom.)
• Consequence: PRKAR1A ENST00000358598 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.87

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 17-68512102-C-A is Benign according to our data. Variant chr17-68512102-C-A is described in ClinVar as [Benign]. Clinvar id is 1295447.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.937 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRKAR1A	NM_001369389.1	c.-180C>A		5_prime_UTR_variant	1/12		NP_001356318.1
PRKAR1A	NM_212471.3	c.-47C>A		5_prime_UTR_variant	1/11		NP_997636.1
PRKAR1A	NM_001278433.2	c.-6-3292C>A		intron_variant			NP_001265362.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRKAR1A	ENST00000358598	c.-47C>A		5_prime_UTR_variant	1/11	1		ENSP00000351410.1
PRKAR1A	ENST00000589017	c.-180C>A		5_prime_UTR_variant	1/12	3		ENSP00000465445.2
PRKAR1A	ENST00000592800	c.-47C>A		5_prime_UTR_variant	1/10	2		ENSP00000466314.2
ENSG00000267009	ENST00000590353.1	n.174-3292C>A		intron_variant		4

Frequencies

GnomAD3 genomes AF: 0.730 AC: 110827 AN: 151816 Hom.: 40634 Cov.: 31

Gnomad AFR AF: 0.695

Gnomad AMI AF: 0.763

Gnomad AMR AF: 0.767

Gnomad ASJ AF: 0.715

Gnomad EAS AF: 0.959

Gnomad SAS AF: 0.775

Gnomad FIN AF: 0.761

Gnomad MID AF: 0.725

Gnomad NFE AF: 0.718

Gnomad OTH AF: 0.751

GnomAD4 exome AF: 0.760 AC: 1714 AN: 2256 Hom.: 658 Cov.: 0 AF XY: 0.751 AC XY: 1217 AN XY: 1620

Gnomad4 AFR exome AF: 0.625

Gnomad4 AMR exome AF: 0.769

Gnomad4 ASJ exome AF: 0.750

Gnomad4 EAS exome AF: 0.956

Gnomad4 SAS exome AF: 0.795

Gnomad4 FIN exome AF: 0.741

Gnomad4 NFE exome AF: 0.751

Gnomad4 OTH exome AF: 0.805

GnomAD4 genome AF: 0.730 AC: 110905 AN: 151934 Hom.: 40657 Cov.: 31 AF XY: 0.734 AC XY: 54494 AN XY: 74266

Gnomad4 AFR AF: 0.694

Gnomad4 AMR AF: 0.767

Gnomad4 ASJ AF: 0.715

Gnomad4 EAS AF: 0.959

Gnomad4 SAS AF: 0.776

Gnomad4 FIN AF: 0.761

Gnomad4 NFE AF: 0.718

Gnomad4 OTH AF: 0.750

Alfa AF: 0.724 Hom.: 38700

Bravo AF: 0.730

Asia WGS AF: 0.862 AC: 2998 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 14, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	1.1
DANN	Benign	0.75
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		3.3

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: rs8080306; hg19: chr17-66508243;